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Benzenediol lactones: a class of fungal metabolites with diverse structural features and biological activities
Accepted Manuscript Benzenediol lactones: a class of fungal metabolites with diverse structural features and biological activities Weiyun Shen , Hongqiang Mao , Qian Huang , Jinyan Dong PII:
S0223-5234(14)01111-8
DOI:
10.1016/j.ejmech.2014.11.067
Reference:
EJMECH 7562
To appear in:
European Journal of Medicinal Chemistry
Received Date: 29 July 2014 Revised Date:
4 November 2014
Accepted Date: 26 November 2014
Please cite this article as: W. Shen, H. Mao, Q. Huang, J. Dong, Benzenediol lactones: a class of fungal metabolites with diverse structural features and biological activities, European Journal of Medicinal Chemistry (2015), doi: 10.1016/j.ejmech.2014.11.067. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT[Benzenediol lactones]
TITLE PAGE
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Benzenediol lactones: a class of fungal metabolites with
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diverse structural features and biological activities
4
Weiyun Shen, Hongqiang Mao, Qian Huang & Jinyan Dong*
Key Laboratory of Eco-environments in Three Gorges Reservoir Region (Ministry of Education), School of Life Science, Southwest University, Chongqing 400715, People's Republic of China
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*E-mail: [email protected], Tel: 86-023-68252400
Abstract: Benzenediol lactones are a structurally variable family of fungal polyketide metabolites possessing a macrolide core structure fused into a resorcinol aromatic ring. These compounds are
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widespread in fungi mainly in the genera such as Aigialus, Cochliobolus, Curvularia, Fusarium, Humicola, Lasiodiplodia, Penicillium and Pochonia etc. Most of these fungal metabolites were reported to possess several interesting biological activities, such as cytotoxicities, nematicidal properties, inhibition of various kinases, receptor agonists, anti-inflammatory activities, heat shock response and immune system modulatory activities etc. This review summarizes the research on the isolation, structure elucidation, and biological activities of the benzenediol lactones, along with some available structure–activity relationships, biosynthetic studies, first syntheses, and syntheses that lead to the revision of structure or stereochemistry, published up to the year of 2014. More than 190
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benzenediol lactones are described, and over 300 references cited. Keywords: Secondary metabolites; Benzenediol lactones; Dihydroxyphenylacetic acid lactones;
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Resorcylic acid lactones; Bioactivities; Structure-activity relationships.
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
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Fungi have been proved to be a fertile and important biosource of numerous secondary metabolites with a huge variety of chemical structures and diverse bioactivities. Fungal metabolites are of considerable synthetic interest and remarkable importance as new lead compounds for medicine as well as for plant protection. Importantly, fungal polyketides are one of the largest and most structurally diverse classes of naturally occurring compounds, ranging from simple aromatic metabolites to complex macrocyclic lactones [1-8].
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Among these polyketide secondary metabolites, benzenediol lactone (BDL) is a growing class which is defined by a 1, 3- benzenediol moiety bridged by a macrocyclic lactone ring [9]. They represent a rich scaffold for structural variation, which differ particularly in the degree and positioning of oxidation and unsaturation about the macrolactone ring. Meanwhile, the phenolic hydroxyl groups on the benzene ring can be methylated. The BDL family may be split into resorcylic acid lactones (RALs) and dihydroxyphenylacetic acid lactones (DALs) based on a substituted resorcinol fragment
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fused to α, β-, and β, γ-positions of the macrocyclic lactone ring, respectively (Fig. 1) [10, 11]. To better describe these structures, there exist different numbering systems. Take 14-membered RALs for example, the older system uses the numbers 1-6 for the aromatic ring and 1'-12' for the aliphatic
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macrocycle, whereas the more recent IUPAC system counts the C-atoms from 1-18 (Fig. 2). This situation, although unsatisfactory, did not cause major problems to date, because the number of BDLs was quite limited [12]. Considering the coherence of the previous review, here we retain both systems. Fig. 1. Basic scaffold of benzenediol lactones
Fig. 2. Different numbering systems of 14-membered RALs
23 24 25 26 27 28 29 30 31 32
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1. Introduction
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To date, over 190 natural BDLs were found in numerous fungi mainly belonging to the genera
Aigialus, Cochliobolus, Curvularia, Fusarium, Humicola, Lasiodiplodia, Penicillium and Pochonia etc. Table 1 shows all the natural BDLs discovered including names, fungal sources and references published between the end of 1953 and July 2014. Although these BDLs are anabolited by many different fungal species, they are known to be produced via a pair of similar collaborating iterative polyketide synthases (iPKSs): a highly reducing iPKS (hrPKS) with product that is further elaborated by a nonreducing iPKS (nrPKS) to yield a 1, 3- benzenediol moiety bridged by a macrolactone [11, 13]. Of course, subtle differences exist between the biosynthetic pathways for different compounds. In recent years, these fungal metabolites were reported to exhibit a wide range of significant 2
ACCEPTED MANUSCRIPT[Benzenediol lactones] biological activities such as inhibition of heat shock protein 90 (Hsp90) and kinases [14], as well as antimicrobial [9], cytotoxic [15], antineoplastic [16], and anti-inflammatory activities [17]. In view of their promising biological activities and interesting structural characteristics, BDLs have increasingly received a great deal of research focus. Since the 1970s, a number of synthetic studies on BDLs have been disclosed. The general synthetic routes usually involve olefin metathesis together with some classical chemical reactions (such as the Heck coupling reaction, the Witting reaction, the Mitsunobu reaction, the Stille coupling reaction, Diels-Alder reaction etc) [18].
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Some BDLs have already been mentioned in a number of certain bioactivity reviews [19-23]. However, these authors cover only a fraction of all known BDLs, since their articles naturally omit the compounds with other activities not included in their reviews. In addition, the resorcylic acid lactones containing a cis-enone or with kinase inhibitory activities of this family have been frequently reviewed by several authors [24-26]. In 2007, Winssinger and Barluenga published a topical review article
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focused on the biosynthesis, chemical synthesis, and biological activity of RALs covered the literature up to 2007. Yet, it only described ten typical RALs in detail [9]. Recently, a review from Xu et al. [18] described 60 resorcinolic macrolides concerning their isolation, bioactivities, biosyntheses, and representative chemical syntheses in recent decades. According to their literature, over 60 different
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resorcinolic macrolides are produced by fungi. However, we found a significantly higher number of relevant fungal metabolites up to 2014: Around 190 compounds are presented in this review. In this review we survey the chemical and biological literatures regarding the isolation, structure elucidation, biological activities, biosyntheses, and chemical syntheses of BDL derivatives from nature. Additionally, those available structure-activity relationships and action mechanisms of some bioactive compounds will also be discussed. We focus on work that has appeared in the literatures up to July 2014. We also hope that we can provide some references for further development and utilization of this
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kind of natural compounds. For ease of illustration and comparison, these natural products are divided into six subclasses according to their ring sizes and structural characteristics: 8-membered BDLs, 10-membered BDLs, 12-membered BDLs, 13-membered BDLs, 14-membered BDLs and other BDLs. Table 1. Benzenediol lactones (BDLs) Name (stereochemistry) (alternative name)
Producing Species
References
Coryoctalactone A (1)
Corynespora cassiicola
[27]
Coryoctalactone B (2)
Corynespora cassiicola
[27]
Coryoctalactone C (3)
Corynespora cassiicola
[27]
Coryoctalactone D (4)
Corynespora cassiicola
[27]
Coryoctalactone E (5)
Corynespora cassiicola
[27]
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Benzenediol octalactone
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Benzenediol decalactone Sporostatin (6)
Sporormiella sp.
[28]
Xestodecalactone A (7)
Penicillium cf. montanense
[31]
Xestodecalactone B (8)
Penicillium cf. montanense
[31]
Xestodecalactone C (9)
Penicillium cf. montanense
[31]
Xestodecalactone D (10)
Corynespora cassiicola
[36]
Xestodecalactone E (11)
Corynespora cassiicola
[36]
Xestodecalactone F (12)
Corynespora cassiicola
[36]
(3R,5R)-Sonnerlactone (13)
Zh6-B1
[37]
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ACCEPTED MANUSCRIPT[Benzenediol lactones] (3R,5S)-Sonnerlactone (14)
Zh6-B1
[37]
Relgro (15)
Fusarium sp.
[40]
Lasiodiplodia theobromae
[56]
Sarocladium kiliense
[72]
Syncephalastrum racemosum
[70]
unidentified endophytic fungus
[27]
Lasiodiplodia theobromae
[56]
(3R)-Lasiodiplodin (16)
(R)-de-O-Methyllasiodiplodin (17)
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12-Membered benzenediol lactones
Syncephalastrum racemosum
[70]
unidentified endophytic fungus
[27]
5-oxo-Masiodiplodin (18)
Lasiodiplodia theobromae
[58]
(3R, 5R)-Hydroxylasiodiplodin (19)
Lasiodiplodia theobromae
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Syncephalastrum racemosum
[58] [70]
Lasiodiplodia theobromae
[58]
Sarocladium kiliense
[73]
(3R, 4S)-4-Hydroxylasiodiplodin (21)
Lasiodiplodia theobromae
[58]
(3R, 5R)-5-Hydroxyl-de-O-methyllasiodiplodin (22)
Lasiodiplodia theobromae
[58]
unidentified endophytic fungus
[27]
Lasiodiplodia theobromae
[58]
Lasiodiplodia theobromae
[59]
unidentified endophytic fungus
[27]
Syncephalastrum racemosum
[70]
unidentified endophytic fungus
[27]
Lasiodiplodia theobromae
[68]
(3R,4R)-4-Hydroxy-de-O-methyllasiodiplodin (28)
Lasiodiplodia theobromae
[69]
(E)-9-Etheno-de-O-methyllasiodiplodin (29)
Lasiodiplodia theobromae
[69]
(3R, 5S)-5-Hydroxyl-de-O-methyllasiodiplodin (30)
Syncephalastrum racemosum
[70]
(3S, 6R)-6-Hydroxylasiodiplodin (31)
Sarocladium kiliense
[73]
Curvularin (32)
Alternaria cinerariae
[77]
Alternaria zinniae
[78]
Ascochytula obiones
[79]
Beauveria bassiana
[80]
Chrysosporium lobatum
[84]
Cochliobolus spicifer
[81]
Curvularia eragrostidis
[83]
Curvularia inaequalis
[82]
Curvularia lunata
[76]
Curvularia pallescens
[83]
Drechslera australiensis
[85]
Eupenicillium sp.
[86]
Helminthosporium maydis
[87]
Penicillium baradicum
[89]
Penicillium gilmanii
[88]
Penicillium sumatrense
[92]
(3R, 6R)-6-Hydroxyl-de-O-methyllasiodiplodin (23) (3R, 6S)-6-Hydroxylasiodiplodin (24) 6-oxo-de-O-Methyllasiodiplodin (25)
(E)-9-Etheno-lasiodiplodin (26)
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Botryosphaeriodiplodin (27)
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(3R, 5S)-Hydroxylasiodiplodin (20)
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ACCEPTED MANUSCRIPT[Benzenediol lactones] [91, 108, 121]
Ulocladium sp.
[94]
α, β-Dehydrocurvularin (33)
Alternaria macrospora
[78]
(also named trans-dehydrocurvularin, dehydrocurvularin)
Alternaria cucumerina
[105]
Alternaria cinerariae
[107]
Alternaria zinniae
[109]
Alternaria tomato
[106]
Aspergillus sp.
[110]
Aspergillus terreus Chrysosporium lobatum Curvularia eragrostidis Curvularia lunata
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Curvularia pallescens
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Penicillium citreo-viride
[111] [84] [83] [76]
[83];
[113]
Drechslera australiensis
[85]
Eupenicillium sp.
[86]
Helminthosporium maydis
[87]
Nectria galligena
[114]
Penicillium turbatum
[90]
Penicillium citreo-viride
[108]
Stemphylium radicinum
[115]
9F series marine fungi
[116]
Ulocladium sp.
[94]
Aspergillus terreus
[114]
Penicillium sp.
[122]
Penicillium citreo-viride
[108]
Penicillium sp.
[112]
Alternaria tomato
[106]
Penicillium citreo-viride
[108]
Penicillium sp.
[112]
Aspergillus terreus
[111]
Penicillium sp.
[122]
Penicillium citreo-viride
[108]
Penicillium sp.
[112]
Curvularia oryzae
[125]
Penicillium citreo-viride
[108]
Penicillium sp.
[112]
Cis-dehydrocurvularin (36)
Penicillium citreo-viride
[91, 108, 121]
12-oxo-Curvularin (37)
Aspergillus sp.
[110]
(also named 7-oxo-curvularin)
Penicillium citreo-viride
[91, 108, 121]
11-β-Hydroxy-12-oxo-curvularin (38)
Aspergillus sp.
[110]
(also named 8-β-Hydroxy-7-oxo-curvularin)
Penicillium citreo-viride
[91, 108, 121]
Penicillium sp.
[112]
Penicillium citreo
[91, 108, 121]
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Cercospora scirpicola
11-α- Hydroxycurvularin (34a)
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11-β- Hydroxycurvularin (34b)
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11-Hydroxycurvularin (34)
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11-Methoxycurvularin (35)
11-α-Methoxycurvularin (35a)
11-β-Methoxycurvularin (35b)
11, 12- Dihydroxycurvularin (39)
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ACCEPTED MANUSCRIPT[Benzenediol lactones] Penicillium citreo
[91, 108, 121]
Citreofuran (41)
Penicillium citreo-viride
[91, 108, 121]
Penilactone (42)
Penicillium sp.
[126]
10,11-Epoxycurvularin (43)
Penicillium sp.
[126]
β,γ-Dehydrocurvularin (44)
Aspergillus sp.
[110]
E-6-Chloro-10, 11-dehydrocurvularin (45)
Cochliobolus spicifer
[81]
11-O-Acetyldehydrocurvularin (46)
Cercospora scirpicola
[113]
Curvularin-7-O-β-D-glucopyranoside (47)
Beauveria bassiana
[80]
Curvularin-4'-O-methyl-7-O-β-D-glucopyranoside (48)
Beauveria bassiana
6-Hdroxycurvularin-4'-O-methyl-6-O-β-D-glucopyranoside
Beauveria bassiana
(49) Oxacyclododecindione (50)
Exserohilum rostratum
(+)-(15R)-10,11-E-Dehydrocurvularin (51)
Curvularia sp.
(+)-(15R)-12-Hydroxy-10,11-E-dehydrocurvularin (52)
Curvularia sp.
(+)-(15R)-13-Hydroxy-10,11-E-dehydrocurvularin (53)
Curvularia sp.
(+)-(11S,15R)-11-Hydroxycurvularin (54)
Curvularia sp.
(+)-(11R,15R)-11-Hydroxycurvularin (55)
Curvularia sp.
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12-Hydroxy-10, 11- trans- dehydrocurvularin (40)
[80] [80]
[127]
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[128] [128] [128] [128] [128]
Curvularia sp.
[128]
Curvularia sp.
[129]
Penicillium sumatrense
[130]
Penicillium sumatrense
[130]
Penicillium sumatrense
[130]
Drechslera phlei
[133]
Penicillium sp.
[131, 135]
Pyrenophora teres
[132]
Drechslera phlei
[133]
Penicillium roseopurpureum
[136]
Penicillium sp.
[131, 135]
Pyrenophora teres
[132]
Drechslera phlei
[133]
Penicillium sp.
[135]
Acremonium zeae
[134]
Drechslera phlei
[133]
Penicillium sp.
[135]
Acremonium zeae
[134]
(R)-7- Methoxydihydroresorcylide (65)
Penicillium sp.
[135]
(S)-7- Methoxydihydroresorcylide (66)
Penicillium sp.
[135]
Dihydroresorcylide (67)
Acremonium zeae
[134]
(68)
Aigialus parvus
[144]
(69)
Aigialus parvus
[144]
Aigialomycin A (70)
Aigialus parvus
[143]
Aigialomycin B (71)
Aigialus parvus
[143]
(+)-(15R)-12-Oxocurvularin (56) Curvulone A (57) Sumalarins A (58) Sumalarins B (59) Sumalarins C (60)
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Trans- resorcylide (61)
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Cis-resorcylide (62)
AC C
(R)-7-Hydroxydihydroresorcylide (63)
(S)-7-Hydroxydihydroresorcylide (64)
13-Membered benzenediol lactones
14-Membered benzenediol lactones
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ACCEPTED MANUSCRIPT[Benzenediol lactones] [157]
Cochliobolus lunatus
[158]
Aigialus parvus
[143]
Paecilomyces sp.
[157]
Aigialus parvus
[143]
Fusarium sp.
[156]
Paecilomyces sp.
[219]
Aigialomycin E (74)
Aigialus parvus
[143]
Aigialomycin F (75)
Aigialus parvus
Aigialomycin C (72)
Aigialomycin D (73)
Paecilomyces sp. Aigialomycin G (76)
Aigialus parvus
1', 2'-Epoxyaigialomycin D (77)
Hypomyces subiculosus
SC
Paecilomyces sp.
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Paecilomyces sp.
[144] [157] [144] [155] [157]
Cochliobolus lunatus
[158]
Caryospomycins A (79)
Caryospora callicarpa
[159]
Caryospomycins B (80)
Caryospora callicarpa
[159]
Caryospomycins C (81)
Caryospora callicarpa
[159]
Cochliobolus lunatus
[161]
Cochliobolus lunatus
[161]
Cochliobolus lunatus
[161]
Cochliobolus lunatus
[158]
Cochliobolus lunatus
[158]
Cochliobolus lunatus
[158]
Hamigera avellanea
[142]
Hamigera avellanea
[142]
Hamigera avellanea
[165]
Hamigera avellanea
[165]
Hamigera avellanea
[165]
Hamigera avellanea
[165]
Hamigeromycin G (94)
Hamigera avellanea
[165]
Hypothemycin (95)
Aigialus parvus
[143]
Coriolus versicolor
[168]
Hypomyces subiculosis
[155]
Hypomyces trichothecoides
[173, 174]
Phoma sp.
[171]
7', 8'-Dihydrohypothemycin (96)
Hypomyces trichothecoides
[174]
5'-O-Methylhypothemycin (97)
Phoma sp.
[171]
L-783,277 (98)
Phoma sp.
[182]
L-783,290 (99)
Phoma sp.
[182]
4-O-Demethylhypothemycin (100)
Aigialus parvus
[143]
Hypomyces subiculosus
[155]
(101)
Hypomyces subiculosus
[155]
(102)
Hypomyces subiculosus
[155]
Monorden (103)
Chaetomium chiversii
[193]
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Deoxyaigialomycin C (78)
Cochliomycin A (82) Cochliomycin B (83) Cochliomycin C (84) Cochliomycin D (85) Cochliomycin E (86) Cochliomycin F (87)
Hamigeromycin B (89) Hamigeromycin C (90) Hamigeromycin D (91) Hamigeromycin E (92)
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Hamigeromycin F (93)
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Hamigeromycin A (88)
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ACCEPTED MANUSCRIPT[Benzenediol lactones] Colletotrichum graminicola
[194]
Humicola fuscoatra,
[200]
Humicola sp.
[195, 196]
Monocillium nordinii
[183, 213]
Neocosmospora sp.
[218]
Neonectria radicicola
[184]
Neophaeosphaeria quadriseptata
[193, 197]
Paecilomyces sp.
[157]
Pochonia chlamydosporia
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(also named radicicol, or monorden A)
Penicillium luteo-aurantium
[222] [198] [199]
Humicola sp.
Tetrahydromonorden (104)
[196]
SC
(also named monorden B) Humicola sp.
Monorden D (106)
Humicola sp.
(also named pochonin D)
Pochonia chlamdosporia
[212]
Monorden E (107)
Humicola sp.
[196]
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Monorden C (105)
[196] [196]
Chaetomium chiversii
[193];
Colletotrichum graminicola
[194]
Monocillium nordinii
[213, 214]
Paraphaeosphaeria quadriseptata
[193, 197]
Colletotrichum graminicola
[194]
Monocillium nordinii
[213, 214]
Neocosmospora sp.
[218]
Pochonia chlamydosporia
[212]
Colletotrichum graminicola
[194]
Monocillium nordinii
[213, 214]
Pochonia chlamydosporia
[212]
Monocillium nordinii
[213, 214]
Neocosmospora sp.
[218]
Humicola fuscoatra
[205]
Penicillium sp.
[204]
Monocillium nordinii
[213, 214]
Nordinone (113)
Monocillium nordinii
[214]
Nordinonediol (114)
Monocillium nordinii
[214]
Monocillin II glycoside (115)
Pochonia chlamydosporia
[212]
Monorden analogue-1 (116)
Humicola fuscoatra
[200]
Pochonia chlamdosporia
[216]
Radicicol B (117)
Humicola fuscoatra
[217]
Radicicol C (118)
Humicola fuscoatra
[217]
Radicicol D (119)
Humicola fuscoatra
[217]
Neocosmosin A (120)
Neocosmospora sp.
[218]
Neocosmosin B (121)
Neocosmospora sp.
[218]
Monocillin I (108)
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Monocillin II (109)
Monocillin III (110)
AC C
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Monocillin IV (111)
Monocillin V (112)
(also named tetrahydromonocillin I)
8
ACCEPTED MANUSCRIPT[Benzenediol lactones] Neocosmospora sp.
[218]
Paecilomycin A (123)
Paecilomyces sp.
[219]
Paecilomycin B (124)
Paecilomyces sp.
[219]
Paecilomycin C (125)
Paecilomyces sp.
[219]
Paecilomycin D (126)
Paecilomyces sp.
[219]
Paecilomycin E (127)
Paecilomyces sp.
[219]
Paecilomycin F (128)
Cochliobolus lunatus
[158]
Paecilomyces sp.
[219]
RI PT
Neocosmosin C (122)
Paecilomyces sp.
Paecilomycin H (130)
Paecilomyces sp.
Paecilomycin I (131)
Paecilomyces sp.
Paecilomycin J (132)
Paecilomyces sp.
Paecilomycin K (133)
Paecilomyces sp.
Paecilomycin L (134)
Paecilomyces sp.
[221]
Paecilomycin M (135)
Paecilomyces sp.
[221]
Pochonin A (136)
Pochonia chlamydosporia
[212]
Pochonin B (137)
Humicola fuscoatra
[217]
Pochonia chlamydosporia
[212]
Humicola fuscoatra
[217]
Pochonia chlamydosporia
[212]
Pochonia chlamdosporia
[212, 225]
Pochonia chlamdosporia
[212, 225]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Fusarium sp.
[156]
Humicola fuscoatra
[217]
Pochonia chlamdosporia
[216]
Pochonin O (149)
Pochonia chlamdosporia
[216]
Pochonin P (150)
Pochonia chlamdosporia
[216]
LL-Z1640-1 (151)
Lederle Culture 21640
[231]
(also named L-783,279)
Cochliobolus lunatus;
[161]
Drechslera portulacae;
[234]
filamentous fungus(MSX63935)
[15]
Paecilomyces sp.
[157]
Sterile fungus (MF6280&6293)
[235]
LL-Z1640-2 (152)
Lederle Culture 21640
[231]
(also named C292, 5Z-7-oxo-zeaenol or L-783,278)
Cochliobolus lunatus
[161, 233]
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SC
Paecilomycin G (129)
Pochonin C (138)
Pochonin D (106) (also named Monorden D ) Pochonin E (139)
TE D
Pochonin F (140) Pochonin G (141) Pochonin H (142) Pochonin I (143) Pochonin J (144)
Pochonin L (146) Pochonin M (147)
AC C
Pochonin N (148)
EP
Pochonin K (145)
[157] [157] [157] [221] [221]
9
ACCEPTED MANUSCRIPT[Benzenediol lactones] [15, 233]
Sterile fungus (MF6280&6293)
[235]
LL-Z1640-3 (153)
Lederle Culture 21640
[231]
LL-Z1640-4 (154)
Lederle Culture 21640
[231]
Zeaenol (155)
Cochliobolus lunatus
[232]
Drechslera portulacae
[234]
filamentous fungus (MSX63935)
[15]
Paecilomyces sp.
[157]
(5E)-7-oxo-Zeaenol (156)
Cochliobolus lunatus
(also named (7'E)-6'-oxozeaenol)
Drechslera portulacae
RI PT
filamentous fungus (MSX63935)
[158, 233] [234] [15]
5,6-Dihydo-5-methoxy-7-oxo-zeaenol (157)
Cochliobolus lunatus
[233]
15-O-Desmethyl-(5Z)-7-oxozeaenol (158)
filamentous fungus (MSX63935)
Zearalenone (ZEA, ZEN) (159)
Fusarium sp.
SC
filamentous fungus (MSX63935)
[15]
[ 242, 277, 279] [220]
13-Formyl-zearalenone (5-formylzearalenone) (160)
Fusarium graminearum
[277]
5, 6-Dehydro-zearalenone (7'-dehydrozearalenone ) (161)
Fusarium graminearum
[277]
Cochliobolus lunatus
[40]
Paecilomyces sp.
[220]
Fusarium graminearum
[271, 272]
Fusarium graminearum
[277];
Streptomyces rimosus
[286]
Penicillium sp.
[300]
Fusarium graminearum
[277]
5-Hydroxy-zearalenol (6' 8'-Dihydroxyzearalene) (163)
Fusarium graminearum
[275]
10-Hydroxy-zearalenone (3'-Hydroxyzearalenones) (164)
Fusarium graminearum
[276]
Fusarium sp.
[273, 274, 277]
Zearalanone (166)
Fusarium sp.
[277]
α-Zearalanol (also named zeranol) (167a)
Fusarium sp.
[277]
Cis-zearalenone (168)
Fusarium sp.
[277]
Cis-α-zearalenol (169a)
Fusarium sp.
[277]
Cunninghamella bainieri
[286]
Cunninghamella bainieri
[286]
Mucor bainieri;
[291, 292, 287, 290]
M AN U
Paecilomyces sp. SC0924
5-Hydroxy-zearalenone (162)
5-Hydroxy-zearalenone (8'-hydroxyzearalenone, F-5-3) (162a)
TE D
5-Epi-hydroxy-zearalenone (8'-Epi-hydroxy-zearalenon, F-5-4) (162b)
10-α-Hydroxy-zearalenone (164a)
EP
10-β -Hydroxy-zearalenone (164b) Zearalenol (ZOL) (165)
α-Zearalenol (165a)
AC C
β-Zearalenol (165b)
β-Zearalanol (also named taleranol) (167b)
Cis-β-zearalenol (169b) 14, 16-Dimethoxyzearalenone (2,4-dimethoxyzearalenone) (170) 16-Methoxyzearalenone
(2-methoxyzearalenone) (171)
Zearalenone-14-β- D-glucopyranoside (172)
Rhizopus sp.; Thamnidium elegans
10
ACCEPTED MANUSCRIPT[Benzenediol lactones] Fusarium graminearum
[288]
5'-Hydroxyzearalenol (174)
Fusarium sp.
[40, 288]
8'-Hydroxyzearalanone (175)
Penicillium sp.
[300]
2'-Hydroxyzearalanol (176)
Penicillium sp.
[300]
Zearalenone-11, 12-oxide (177)
Fusarium graminearum
[301]
Zearalenone-11, 12-dihydrodiol (178)
Fusarium graminearum
[301]
10-Oxo-zearalenone (10-keto-ZEA) (179)
Fusarium graminearum
[301]
5'-Hydroxyzearalenone (180)
Fusarium sp.
[40]
Trans-7', 8'-dehydrozearalenol (181)
Paecilomyces sp.
Radicicol A (182)
Cochliobolus lunatus
(also named 89-250904-F1)
Hamigera avellanea
Ro 09-2210 (183)
Curvularia sp.
Queenslandon (184)
Chrysosporium queenslandicum
Cryptosporiopsin A (185)
Cryptosporiopsis sp.
[309]
Y5-02-B (186)
Unknown
[310]
Y5-02-C (187)
Unknown
Apralactone A (188)
Curvularia sp.
[128]
Menisporopsis theobromae
[311]
2. Overview of BDLs
[220] [233] [142] [306] [307]
[310]
2.1 8-Membered benzenediol lactones (Benzenediol octalactones)
TE D
Fig. 3. The structures of 8-membered benzenediol lactones (benzenediol octalactones)
To date, coryoctalactones A–E (1-5) (Table 1 and Fig. 3), isolated from Corynespora cassiicola
EP
(JCM 23.3), an endophyte of the mangrove plant Laguncularia racemosa (Combretacaeae) from the island of Hainan, China are the only members of benzenediol octalactones [27]. The relative stereochemistry of coryoctalactones were determined on the basis of one and two-dimensional NMR spectroscopy as well as by high resolution mass spectrometry. The absolute configuration of the side
AC C
5 6 7 8 9 10 11 12 13 14 15 16 17 18
SC
M AN U
Menisporopsin A (189)
1 2 3 4
RI PT
Zearalenone-14-sulfate (ZEN-4-sulfate) (173)
chain hydroxyl C in 1–3 and 5 were tentatively assigned as “R” based on biogenetic consideration in comparison with xestodecalactones D–F. Moreover, the comparison of the optical rotation value of 3 with those of 1 and 2 as well as comparison of NMR data of C-9 and H-9 indicated that 2 and 3 share identical configuration at C-9, and 1 and 2 are epimers at C-9. All isolated compounds were evaluated for their antimicrobial, cytotoxic, and antitrypanosomal activities, but no significant results were obtained. 2.2 10-Membered benzenediol lactones (benzenediol decalactones) Fig. 4. The structures of 10-membered benzenediol lactones (benzenediol decalactones)
11
RI PT
ACCEPTED MANUSCRIPT[Benzenediol lactones]
To data, only ten examples of 10-membered benzenediol lactones have been reported, from marine or terrestrial fungi, namely, sporostatin (6), xestodecalactones A-F (7-12), sonnerlactones (13-14), relgro (15) (Table 1 and Fig. 4). Among them relgro and sonnerlactones belong to
M AN U
10-membered RALs and the other compounds belong to 10-membered DALs.
The first natural 10-membered benzenediol lactone, sporostatin (6), was isolated from the fermentation filtrate of the fungus, Sporormiella sp. M5032 in 1997 by Kinoshita et al [28]. The structure of 6 was secured by an X-ray diffraction study [28], but the absolute configuration was reported by its first total synthesis in 2009 [29]. Sporostatin has been found to have an inhibitory effect on cyclic adenosine 3', 5'-monophosphate phosphodiesterase (cAMP-PDE) with an IC50 value of 41 µg/mL. Further biological evaluation indicated that 6 was a specific kinase inhibitor in vitro whose IC50
TE D
values were 0.1 µg/mL for EGF receptor kinase, 3 µg/mL for ErbB-2, and 100 µg/mL or greater for other kinases, including the platelet derived growth factor (PDGF) receptor, ν-src and protein kinase. Kinetic analyses revealed that inhibition of EGF receptor kinase and cAMP-PDE by sporostatin was noncompetitive either with substrate or with ATP [28, 30]. The xestodecalactones A-C (7-9) were secondary metabolites of a fungus Penicillium cf.
EP
montanense obtained from the marine sponge Xestospongia exigua, and the constitutions, stereostructures including the relative configurations of 8 and 9 were initially established using online HPLC-NMR, ESI-MS/MS, and CD spectra analysis after isolating these compounds [31]. The absolute configurations at C-11 of 7-9 were initially reported as S; however, they were later revised as R until
AC C
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
SC
1
their total syntheses were accomplished and reported during the period 2004 to 2007 [32-34]. Xestodecalactone B produced 25, 12, 7 mm inhibition zones against Candida albicans at 100, 50, 20 µmol, respectively [31]. It was also noted that xestodecalactone A has been patented for antitumor activity [35]. In 2012, the chemical investigation on the ethyl acetate extract of C. cassiicola from leaf tissues of the mangrove plant L. racemosa collected at Hainan Island in China, led to the isolation of xestodecalactones D–F (10-12) [36]. The structures of 10-12 were determined by analysis of NMR and MS data. The relative configuration of xestodecalactone D was obtained from a careful analysis of the coupling constants observed in the well resolved 1D 1H NMR spectrum, as well as from ROESY correlations. Their absolute configurations were assigned by TDDFT ECD calculations of their solution conformers, proving that they belong to the (11S) series of xestodecalactones, opposite to the (11R) configuration of the known xestodecalactones A–C. In this paper, the cytotoxic, antibacterial, antifungal and antitrypanosomal activity of these compounds were investigated, but no positive results 12
ACCEPTED MANUSCRIPT[Benzenediol lactones] were obtained. In 2010, two new metabolites, (3R, 5R)-sonnerlactone (13) and (3R, 5S)-sonnerlactone (14), were isolated from the mangrove endophytic fungus strain Zh6-B1 obtained from the bark of Sonneratia apetala growing in Zhuhai, Guangdong, China [37]. The absolute configuration of 13 was determined by single-crystal X-ray analysis and spectroscopic data. While 14 was deduced by NOESY analysis and comparing circular dichroism spectroscopy with compound 13. Both sonnerlactones (13, 14) exhibited weak anti-proliferative activity against multidrug-resistant human oral floor carcinoma cell lines
RI PT
(KV/MDR) (42.4% and 41.6%, respectively, at 100 µM). The stereoselective synthesis of 13 and 14 has been accomplished starting from L-aspartic acid [38]. The key steps involved asymmetric allylation, Alder–Rickert reaction and Mitsunobu macrolactonization.
Apart from the natural benzenediol decalactones as described above, a novel compound, relgro (15), was mentioned incidentally as an artificial product for the purpose of active test in 1973 [39]. Up
SC
to 2011, it was isolated and elucidated together with other 14-membered RALs from the seagrass-derived fungus Fusarium sp. PSU-ES73 [40]. Antimicrobial activity test showed that it was inactive against S. aureus ATCC25923, methicillin-resistant S. aureus SK1 and Cryptococcus 14-membered RALs together isolated. 2.3 12-Membered benzenediol lactones
M AN U
neoformans ATCC90113. We presumed that the structure may be related to the rearrangement from the
The number of natural 12-membered benzenediol lactones reported by July of 2014 is 53. This group is distributed in more than 30 species and can be divided into three subgroups: lasiodiplodin macrolides (RAL12), curvularin macrolides (DAL12) and other 12-membered benzenediol lactones. Lasiodiplodin macrolides (RAL12)
Fig. 5. The structures of lasiodiplodin macrolides (RAL12)
AC C
EP
TE D
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
24 25 26
To date, 16 lasiodiplodins, 16-31 (Table 1 and Fig. 5), have been produced by fungi Lasiodiplodia theobromae (syns. Botryodiplodia theobromae and Diplodia gossypina, teleomorph Botryosphaeria 13
ACCEPTED MANUSCRIPT[Benzenediol lactones] rodina), Sarocladium kiliense and Syncephalastrum racemosum, as well as various plants, Euphorbia splendens [41], Arnebia euchroma [42], E. fidjian [43], Annona dioica [44], Dioclea violacea [45], Durio zibethinus [46], Pholidota yunnanensis [47], Cibotium barometz [48], Osbeckia opipara [49], Ficus nervosa[50], Cyphostemma greveana [51], Ampelopsis japonica [52], Macroptilium lathyroides [53], and Caesalpinia minax [54]. Among them, L. theobromae, the common pathogenic fungi isolated in the tropics and subtropics on a variety of host plants, was found to be a remarkable producer of lasiodiplodins. Additionally, it should be noted that several authors assumed that lasiodiplodins may
RI PT
not be plant metabolites but may be from fungal epiphytes or endophytes [55].
(3R)-Lasiodiplodin (16) and (R)-de-O-methyllasiodiplodin (17) were the first members of 12-membered resorcylic acid lactone (RAL12) subclass of the benzenediol lactone (BDL) family to be discovered and were isolated from the cultural filtrate of L. theobromae S22L by Aldridge et al. in 1971 [56]. Later, another seven metabolites, 5-oxo-lasiodiplodin (18), (3R, 5R)-hydroxylasiodiplodin (3R,
5S)-hydroxylasiodiplodin
(20),
(3R,
4S)-4-hydroxylasiodiplodin
(21),
(3R,
SC
(19),
5R)-5-hydroxyl-de-O-methyllasiodiplodin (22), (3R, 6R)-6-hydroxyl-de-O-methyllasiodiplodin (23) and (3R, 6S)-6-hydroxylasiodiplodin (24) were also isolated from the fermentation broth and mycelium of L. theobromae IFO 31059 [57-59]. The relative configuration of 16 was assigned by single-crystal
M AN U
X-ray, whereas the absolute stereochemistry at C-3, initially deduced to be S from chemical reduction to afford phenyl-2-nonanol, was later revised to R on the basis of the synthetic studies [41, 56, 60-63]. The structures including absolute configurations, of the other compounds from L. theobromae were determined by means of spectroscopic analyses, mainly 1D and 2D NMR, the modified Mosher’s method, and chemical derivation. Especially, the S-configuration of C-3 in compounds 18-20 deduced from the structure of 16 based on the comparisons of spectral data in the previous report [57] also needs to be revised to R. Compounds 18-24 were found be active in potato micro-tuber induction at a
TE D
concentration of 10-3-10-4 M and the activity of 21 was stronger than that of the others [57-59]. We presumed that the hydroxyl was essential for potato micro-tuber inducing activity, and S-configuration has higher activity. The biosynthetic pathways of 16 and 20 in L. theobromae have been studied by Kashima with 13C-labeled acetate tracer experiments [64, 65], and the biosynthetic gene clusters was first identified by Xu et al. [66].
EP
In 2006, two new 12-membered resorcylic acid lactones, namely 6-oxo-de-O-methyllasiodiplodin (25) and E-9-etheno-lasiodiplodin (26), together with 16, 17 and 22, were isolated from the mycelium extracts of an unidentified endophytic fungus (No. ZZF36) obtained from a brown alga (Sargassum sp.) collected from Zhanjiang sea area, China [67]. The structure of 25 was confirmed by X-ray
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
crystallographic analysis. In this paper, (3R)-lasiodiplodin (16), de-O-methyllasiodiplodin (17) showed in vitro antimicrobial active against Staphylococcus aureus, Bacillus subtilis, and F. oxysporum. The bioassay result implied that C-13 and C-15 hydroxyls of lasiodiplodins probably may enhance their antibiotic activities. In 2009, one new lasiodiplodin derivative, named botryosphaeriodiplodin (27) together with 16, 19 and 20, were isolated from an endophytic fungus B. rhodina PSU-M114, which was obtained from the leaves of Garcinia mangostana collected in Suratthani Province, Thailand [68]. The absolute configuration at C-3 in 27 was assumed to analogous to that of 16, while the C-7 stereochemistry was not performed as 27 was obtained in low quantity. In this paper, (3R)-lasiodiplodin (16) exhibited antibacterial activity against S. aureus and methicillin-resistant S. aureus with the respective MIC values of 64 and 128 mg/mL. In 2014, two further lasiodiplodins, (3R, 4R)-4-hydroxy-de-O-methyl-lasiodiplodin (28) and (E)-9-etheno-de-O-methyl-lasiodiplodin (29), together with 17, 23 and 25, from a cytotoxic extract obtained from a culture of L. theobromae, an 14
ACCEPTED MANUSCRIPT[Benzenediol lactones] endophyte from the root tissues of Mapania kurzii (Cyperaceae) from the Malaysian rain forest, were characterized on microgram scale (capillary NMR probe) [69]. The structures including absolute configurations, of the other compounds were determined by means of spectroscopic analyses by analogy with the data for the known lasiodiplodins. The cultural extract was found to biologically active against the P388 murine leukaemia cell line (>80% growth inhibition) [69]. Interestingly, lasiodiplodins isolated from the plant have been previously reported to have antileukemic activities [41].
RI PT
The crude EtOAc extract of the strain S. racemosum from soil in tropical and subtropical regions was found to show cytotoxicity against cholangiocarcinoma cell line KKU-M156 with an IC50 value of 18.02 µg/mL. Bioassay-guided fractionation of this fungal extract led to the isolation of five lasiodiplodins,
(3R,
5S)-5-hydroxy-de-O-methyllasiodiplodin
de-O-methyllasiodiplodin
(17)
(25)
(3R)-lasiodiplodin
5R)-5-hydroxy-de-O-methyllasiodiplodin [70].
Compound
30
showed
(16),
(22)
cytotoxicity
and
against
SC
6-oxo-de-O-methyllasiodiplodin
(3R,
(30),
cholangiocarcinoma, KKU-M139, KKU-M156, and KKU-M213 cell lines with IC50 values in the range of 14.30-19.04 µg/mL, while 17 showed cytotoxicity against KB, BC1, and NCI-H187 cell lines with IC50 values of 12.67, 9.65, and 11.07 µg/mL, respectively. In addition, compound 16 showed
M AN U
cytotoxicity against KB, BC1 and NCI-H187 cell lines with IC50 values of 20.77, 25.89, and 20.89 µg/mL, respectively. The first stereo selective total synthesis of 30 and 22 was finished by Yadav et al in 2010 [71]. In
2013,
Yuan
et
al.
reported
the
isolation
and
structure
elucidation
of
(3S,
6R)-6-hydroxylasiodiplodin (31), (3R)-lasiodiplodin (16), and (3R, 5S)-5-hydroxylasiodiplodin (20) from an endophytic fungus S. kiliense grown in rice medium isolated from the gut of healthy Apriona germari (Hope) collected from the campus of Jiangsu Normal University, Jiangsu Province, China [72].
TE D
The structure of 31 was elucidated by a combination of spectroscopic data interpretation, single-crystal X-ray diffraction analysis, and modified Mosher’s method. The absolute configuration at C-6 was determined by a modified Mosher’s method, based on the analysis of differences in proton chemical shifts between the (R), (+) -and (S), (−)-α-methoxy-α-(trifluoromethyl) phenylacetyl (MTPA) esters of 31. The absolute configuration at C-3 was deduced from the relative configuration of C-3 with C-6 by
EP
the X-ray diffraction analysis. The result indicated S configuration for C-3 in lasiodiplodin analogues also exist in nature.
(3R)-Lasiodiplodin (16) and (R)-de-O-methyllasiodiplodin (17) are the most widely studied metabolites in the lasiodiplodin series. (3R)-Lasiodiplodin (16), isolated from plant C. greveana, was
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
found to be active with IC50=0.045 µg/mL against the A2783 ovarian cancer cell line [51]. In 2007, 16 was revealed to be phytotoxic by blocking the electron transport chain in thylakoids at multiple targets that were different from those of current herbicides [73]. De-O-methyllasiodiplodin (17) obtained in the roots of A. euchroma (a traditional Chinese medicine), was found to be responsible, at least in part, for the pharmacological properties of the plant extracts as the result of its efficient inhibition of prostaglandin biosynthesis [55, 63]. In 2010, 17 was reported to be a potent inhibitor of pancreatic lipase (PL) (IC50=4.73 µmol/L), an enzyme that plays a key role in the efficient digestion of triglycerides and that was a target for treating obesity [74]. In 2011, 17 was found to be a novel, natural, non-steroidal mineralocorticoid receptor (MR) antagonist (IC50= 8.93 µmol/L) and an efficient therapeutic target for the treatment of hypertension and other cardiovascular diseases [75]. In this paper, the authors assumed that the acetylation at phenolic hydroxyl groups in analogs of 17 can increase the antagonistic effect against MR and the ring size of the lactone was also very crucial for its activity [75]. 15
ACCEPTED MANUSCRIPT[Benzenediol lactones] It should be noted that this is the first macrolide compound found to behave as MR antagonist to date, different from the other nonsteroidal MR antagonists. Curvularin macrolides (DAL12) Fig. 6. The structures of curvularin macrolides (DAL12)
AC C
EP
TE D
M AN U
SC
RI PT
1 2 3 4
5 6 7
This group including 30 compounds, 32-60 (Table 1 and Fig. 6), is a subclass of DALs with a 12-membered ring system. These compounds almost apparently stem from varied oxidation levels at 16
ACCEPTED MANUSCRIPT[Benzenediol lactones] the C-11 and C-12 position. They are produced by some fungal species mainly from different ascomycete species including Alternaria, Aspergillus, Curvularia, and Penicillium spp. Curvularin (32), the best known member of the curvularin family, was originally isolated as an antifungal agent from the culture filtrate of a species of Curvularia by Musgrave in 1956 [76] and later reisolated from a number of phytopathogenic fungal genera such as Alternaria [77, 78], Ascochytula [79], Beauveria [80], Cochliobolus [81], Curvularia [82, 83], Chrysosporium [84], Drechslera [85], Eupenicillium [86], Helminthosporium [87], Penicillium [88-93], Ulocladium [94] etc and from the
RI PT
root extract of Patrinia scabra plant [95, 96]. The structure of 32 was established by spectroscopic, X-ray and synthetic studies [97-103] and it was usually synthesized based on the Alder–Rickert strategy [100, 102]. Another well known curvularin-type compound, α, β-dehydrocurvularin (trans-dehydrocurvularin) (33), which features a trans double bond in C-10 - C-11 usually co-occurs with curvularin in fungi [78, 83-85, 90, 104-112]. Besides, it was also independently found from Cercospora scirpicola [113], Nectria galligena [114], Stemphylium radicinum [115] and several 9F
SC
series marine fungi [116]. Early biosynthetic studies supported that α, β-dehydrocurvularin was a polyketide product, which was excreted from the cells and reduced to curvularin by extracelullar enzymes [107, 117]. Recently, Molnár’s group predicted the biosynthesis of 33 and revealed
M AN U
collaborating hrPKS-nrPKS pairs whose efficient heterologous expression in Saccharomyces cerevisiae provided a convenient access to the DAL12 scaffolds [13].
Both curvularin (32) and α, β-dehydrocurvularin (33), have shown non-specific phytotoxic activity e.g. against Zinnia elegans and Cirsium arvense [106-107, 118], selective antimicrobial activity e.g. against B. subtilis, S. aureus, and Escherichia coli [83, 111], inhibition of TGF-b signaling activities (IC50 = 34.2 and 1.7 µM, respectively) [118], cytotoxic activities against different human tumour cell lines like A549 (IC50 = 13.91±0.15 and 2.10±0.33 µM, respectively), HeLa (IC50 = 25.64
TE D
±0.37 and 21.01±0.19 µM, respectively), MDA-MB-231 (IC50 = 1.3±0.37 and 9.34±0.38 µM, respectively) and MCF-7 (IC50 = 21.89±0.19 and 11.19±0.31 µM, respectively) [84]. Additionally, 32 has been revealed to reduce the expression of the proinflammatory enzyme iNOS in a glucocorticoid-resistant model of rheumatoid arthritis by inhibiting the JAK/Stat signaling pathway [96, 119-120]. It also exhibited 80% acetylcholinesterase (AChE) inhibitory activity [84], and had the
EP
antioxidant activity of H. maydis FBF at a high concentration [87]. While compound 33 showed good superoxide anion scavenging activity with an EC50 value of 16.71 µg/mL [84] and it was also active against COLO 205 with an IC50 of 7.9 µM [84]. Taking together, the IC50 values of 33 were almost always one order of magnitude higher than those of 32 against the corresponding test cell lines except
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
for MDA-MB-231 cell line. However, the presence of a double bond is the only structural difference between two compounds (as one counterpart), which might be one of the important structural property essential for effective interaction in the bioactive profiles. Ten new members of the curvularin family, which include 11-α-hydroxycurvularin (34a),
11-β-hydroxycurvularin (34b), cis-dehydrocurvularin
(36),
11-α-methoxycurvularin 12-oxo-curvularin
(37),
(35a), 11-β-methoxycurvularin
(35b),
11-β-hydroxy-12-oxo-curvularin
(38),
11,12-dihydroxycurvularin (39), 12-hydroxy-10,11- trans- dehydrocurvularin (40) and citreofuran (41) together with two known 32 and 33, were isolated from the mycelium of the hybrid strain ME 005 derived from P. citreoviride 4692 and 6200, upon fermentation on rice [91, 108, 121]. Their structures were established by spectroscopic data. It is worth mentioning that citreofuran (41) is a structurally unique octaketide derivative belonging to the curvularin family containing a furan ring. Furthermore, these authors still pointed that the abosolute configuration of the biologically active compound 17
ACCEPTED MANUSCRIPT[Benzenediol lactones] 1
previously isolated from A. tomato in 1976 was β-hydroxycurvularin (34b) [106]. Later,
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
11-hydroxycurvularin (34) and 11-methoxycurvularin (35) (the mixtures of 11α- and 11β-epimers) were also reported as metabolites of several fungi such as A. cervinus [111] and Penicillium sp. [122] (Trichonaceae) isolated from the rhizosphere of Anicasanthus thurberi and Fallugia paradoxa, respectively. The author assumed 34 and 35 was probably produced by a Michael-type addition of H2O and MeOH to the enone system of 33 during the processing of these microorganisms, respectively [111]. In 2007, the first total synthesis of 35a and 35b was reported by Liang et al., in which the
RI PT
spectral data of originally proposed structure for 11-methoxycurvularin were pointed to 35a [123]. The curvularin derivatives 32-41 were discovered to have considerable cytotoxicities toward a panel of human cancer cell lines (NCI-H460, MCF-7, SF-268, MIA. Pa Ca-2), with IC50 values ranging from 0.90 to 13.30 µM [111, 122]. They acted as inhibitors in blocking the cell division [81] by specifically disordering the microtubule centers [102] and inducing barrel-shaped spindles [90], and inhibited
SC
Hsp90 [16], a promising target for anticancer drug discovery (Janin 2005). The ability likely originated from the conformation of their macrocyclic ring, which mimiced the M-helicity of the colchicin skeleton, a stereochemical feature known to be important for tubulin binding of these agents [81, 101]. Compounds, 34, 37 and 38, had nematicidal activities against P. penetrans of 35%, 80% and 23% at a
M AN U
respective concentration of 300mg/L [110, 124]. Moreover, 11-α-methoxycurvularin (35a) was independently identified from the crude extract of C. oryzae MTCC 2605 by silica gel column chromatography in 2009 [125]. In this paper, it showed strong antibacterial activities against gram-positive bacteria e.g. S. aureus, B. sphericus with a mean MIC value of 100 µg/mL and gram-negative bacteria e.g. Pseudomonas aeruginosa, P. oleovorans with inhibition zones between 12 to 16 mm, as well as moderate antifungal activity. Against Spodoptera litura 4th instar larvae LD50 was determined to be 205.59 µg/mL [125].
TE D
Recently, the chemical investigation of the endophytic fungus Penicillium sp. obtained from stem tissues of Limonium tubiflorum (from L. tubiflorum growing in Egypt) resulted in the isolation of two new curvularins, named penilactone (42) and 10,11-epoxycurvularin (43), along with four known curvularin-type metabolites (33, 35a, 35b, 36) [126]. Penilactone (42) is characterized by a 4-chromanone ring system formed by connecting the oxygenated aromatic carbon C-7 and CH-11. It
EP
was noteworthy that 42 incorporated a 4-chromanone ring system was rather rare among macrolides. The configuration of 42 and 43 at C-15 was assumed by comparison the of measured [α]D values with those of similarly curvularin-type metabolites [126]. In this paper, compounds (35a and 35b) showed
AC C
pronounced antitrypanosomal activities with MIC values of 4.96 and 9.68 µM, respectively. Compounds (35a, 35b, 36) selectively inhibited the growth of human T cell leukemia cells (Jurkat) (IC50 = 3.9, 2.3, and 5.5 µM, respectively), and human histiocytic lymphoma cells (U937) (IC50 = 1.8, 4.6, 2.5, and 7.6 µM, respectively), and reduced TNFα-induced NF-κB activation as expressed by their IC50 values of 4.7, 10.1, 5.6, and 1.6 µM, respectively [126]. We presume that the presence of a free methoxy group at C-11 is essential for antitrypanosomal activity, whereas trans isomer is more active than cis one. Other well known curvularin analogues included β, γ-dehydrocurvularin (44) isolated from the culture filtrate and mycelial mats of Aspergillus sp. [110], E-6-chloro-10, 11-dehydrocurvularin (45) from C. spicifer [81], 11-O-acetyldehydrocurvularin (46) from C. scirpicola [113]. 44 showed nematicidal activities against P. penetrans of 35% and 87% at a respective concentration of 300 and 1000 mg/L [110]. In 2005, three new curvularin-derived products were obtained during the course of biotransformation of curvularin (32) with B. bassiana ATCC 7159. They were identified as 18
ACCEPTED MANUSCRIPT[Benzenediol lactones] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
curvularin-7-O-β-D-glucopyranoside (47),
curvularin-4'-O-methyl-7-O-β-D-glucopyranoside (48),
36 37 38 39 40 41 42 43 44
oxa-Michael addition of the phenolic hydroxyl group to the α, β-unsaturated ketone moiety. The
6-hydroxycurvularin-4'-O-methyl-7-O-β-D-glucopyranoside (49) which resulted from hydroxylation, glucosidation, and methylglucosidation of the substrate, respectively [80]. In 2008, a new curvularin analogue, oxacyclododecindione (50), was isolated from the fermentations of the fungal strain Exserohilum rostratum IBWF99121, as a potent inhibitor of IL-4 signaling by inhibiting the binding of the activated Stat6 transcription factors to the DNA binding site without affecting tyrosine phosphorylation [127]. The structure of 50 was determined by a combination of spectroscopic
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techniques. Unfortunately, neither the relative nor the absolute configuration could be determined from the existing data. Later, in a screening for fungal compounds with a cell-based reporter assay, 32, 33 and 50 were found to suppresse the TGF-b inducible activation of a Smad 2/3 dependent transcriptional reporter in HepG2 cells in a dose-dependent manner without displaying cytotoxic effects. Among them, 50 was the most highly potent inhibition with IC50 values of 190-217 nM [119]. We assume that free
SC
methyl groups may enhance the activity.
During the chemical investigation of the cytotoxic extract of the marine-derived fungus Curvularia sp. (strain no. 768), isolated from the red alga Acanthophora spicifera, six novel curvularin-type macrolides, (+)- (15R)- 10,11- E-dehydrocurvularin (51), (+)- (15R)- 12-oxocurvularin (+)- (15R)- 12- hydroxy- 10,11- E- dehydrocurvularin (53), (+)- (15R)- 13- hydroxy- 10,11- E-
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(52),
dehydrocurvularin (54), and C-11 stereocenter epimers of (+)- (15R)- 11- hydroxycurvularin (55 and 56), were obtained together with a 14-membered macrolide. The planar structures of 51-56 were confirmed by interpretation of extensive 1D and 2D NMR experiments (HMBC, HSQC and COSY). Based on their optical rotation and CD spectra, the configuration at C-15 of newly isolated metabolites 51-56 was assigned as R, which was different from the known curvularin-type compounds as described above. The newly identified metabolites 51 and 53-55 were found to exhibit structure-dependent
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cytotoxic properties. Especially, 51 displayed strong cytotoxicity, about 24-fold more cytotoxic potency than its 13-hydroxy derivative 53, against nine tested human cancer cell lines (BXF 1218L (bladder cancer), BXF T24 (bladder cancer), CNXF SF268 (glioblastoma), LXFA 289L (lung adenocarcinoma), MAXF 401NL (mammary cancer), MEXF 462NL (melanoma), MEXF 514L (melanoma), OVXF 899L (ovarian cancer), and PRXF PC3M (prostate cancer)) in a
EP
concentration-dependent manner (IC50 = 1.25 µM), suggesting that the stereochemistry at C-15 chiral center of the curvularin-type macrolides is not crucial for their cytotoxic activity. In contrast, variations of the oxidation levels around the macrocycle seem to influence the cytotoxic activity of the
AC C
(+)-(15R)-curvularin-type metabolites [128]. Curvulone A (57), another novel (15R)-curvularin-type metabolites has been isolated from a Curvularia sp. associated with a marine red alga Gracilaria folifera, with two known 15R series compounds (51 and 54). Structurally, 57 features a unique benzofuranone ring linked to 12-membered macrolactone, which can be formed by an intramolecular relative configurations of two chiral centres were determined as 10S*, 15R* by X-ray diffraction analysis, and the absolute configuration of 57 was accomplished independently by the solid state TD-DFT ECD method and by measuring the anomalous dispersion effect. The metabolites (51, 54 and 57) had pronounced antibacterial activities against the B. megaterium, antifungal activities against Microbotryum violaceum and Septoria tritici, and were antialgal against Chlorella fusca. Particularly, 57 showed the strong activity against the Gram positive bacterium Bacillus strain 6540 inhibiting 92% of the bacterial growth [129]. More recently, in order to find new bioactive secondary metabolites from marine-derived fungi, 19
ACCEPTED MANUSCRIPT[Benzenediol lactones] three rare curvularin derivatives, sumalarins A–C (58-60), along with three known metabolites (32, 33 and 47), were identified in the cytotoxic extract of P. sumatrense MA-92, a fungus obtained from the rhizosphere of the mangrove Lumnitzera racemosa. 58-60 were the first examples of curvularin derivatives possessing sulfur substitution. Their structures were established by a detailed interpretation of NMR and MS data, including determining the crystal X-ray structure of 58. The authors assumed that 60 was likely produced via Michael addition of the cysteine metabolite 3-mercaptolactate to the double bond of dehydrocurvularin and thus was reminiscent of glutathione detoxification of Michael
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acceptors in mammalian metabolism. Compounds 58 and 59 can be derived from 60 by esterification or esterification and acylation, respectively. The bioassay results showed that the sulfur-containing curvularin derivatives 58-60 exhibited cytotoxic activities against seven tested tumor cell lines (Du145, HeLa, Huh 7, MCF-7, NCI-H460, SGC-7901, and SW1990) with IC50 values ranging from 3.8 to 10 µM, while 32 was inactive. The data implied that the structural feature of sulfur substitution at C-11 or Novel 12-membered resorcylides Fig. 7. The structures of novel 12-membered resorcylides
SC
a double bond at C-10 significantly increased the cytotoxic activities of the curvularin analogues [130].
To date, 7 12-membered benzenediol lactones including trans-resorcylide (61), cis-resorcylide (62), dihydroresorcylide (67), 7-hydorxyresorcylide enantiomers (63 and 64), and their methyl esters (65 and 66) (Table 1 and Fig. 7), have been included in this type. They are produced by fungi Penicillium spp. [131], Pyrenophora teres [132], D. phlei [133] and Acremonium (Sarocladium) zeae
EP
[134]. Structurally, they are related to both curvularinds and lasiodiplodins, but possess a modified carbon skeleton [131]. The skeleton of these compounds contains one more ketone carbonyl than lasiodiplodin’s. Meanwhile, the ketone carbonyl in these compounds is linked to the isolated benzylic CH2 corresponding to C-10 rather than directly to the aromatic ring in curvularins.
AC C
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Trans- (61) and cis-resorcylide (62) were first isolated as new plant growth inhibitors from an
unidentified species of Penicillium by Oyama et al. in 1978 [135]. Later, they were reisolated from another fungus Penicillium SC2193 along with 7-hydorxyresorcylide enantiomers (63 and 64), and their methyl esters (65 and 66) [131]. In 1996, 62 has been isolated from P. roseopurpureum [136]. Besides the genus Penicillium, trans- (61) and cis-resorcylide (62) also was found in P. teres, the cause of net-type net blotch of barley [132], and D. phlei, a pathogenic fungus on timothy grass, along with 63 and 64 [133]. The structures of 61-66 were determined using a combination of spectroscopic techniques with emphasis on NMR spectroscopy. The spectral data indicated that 61 and 62 possess a rather unique structural mark: the cis isomer (62) is characterized by a strong H-bond between the phenol hydroxyl and the lactone carbonyl, while trans isomer (61) lacks that feature [135]. The S-configuration at C-3 of resorcylides was originally assigned on the basis of the chemical degradation of cis-resorcylide [135], and this was later confirmed by total synthesis [137]. In 2008, a new 20
ACCEPTED MANUSCRIPT[Benzenediol lactones]
7-hydroresorcylide (64 and 64) [134]. The configuration of a methyl group in 67 had been originally determined to be the S configuration; however, the optical rotation sign of naturally isolated 67 {[α]25.0 D +15.0 (c 0.33, MeOH)} was opposite to that of the synthetic 67 {[α]24.0 –40.0 (c 0.8, MeOH)}, D indicating that the configuration of naturally isolated 67 most likely needs to further revised [138]. Resorcylides were phytotoxic as demonstrated in leaf puncture wound assays and inhibited
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seedling root elongation [132-135, 139]. 61 caused necrosis on corn and crabgrass (Digitaria sanguinalis) at 0.06 µg per leaf. At 2 µg/leaf, timothy (Phleum pratense), wild poinsettia, and sunflower (Helianthus annuus) were also very sensitive to 61, while 62 was inactive at 1 µg per leaf. Other saturated resorcylide (63-66) fell midway between the two and retained activity at 0.5 µg per leaf. Compound 61 was a plant growth inhibitor and was >10 times more effective than 62 at inhibiting
SC
seedling root elongation [135]. Additionally, trans-resorcylide (61) exhibited cytotoxicity against a panel of tumor cell lines, anti-microbial activity against Pyricularia oryzae, and was an inhibitor of 15-hydroxyprostaglandin dehydrogenase, whereas 62 does not inhibit that enzyme [140]. Cis-R-(−)-resorcylide (62) specifically inhibits blood coagulation factor XIIIa and may be
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advantageous to enhance fibrinolysis and resolve blood clots [136, 141]. Apparently, the configuration of double bond has a strong impact on bioactivities. 2.4 13-Membered benzenediol lactones
Fig. 8. The structures of 13-membered benzenediol lactones
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21 22 23 24 25 26 27 28 29
of 154 isolates), a protective endophytic fungus of maize, along with the two diastereomers of
Natural occurring 13-membered 1, 3-dihydroxybenzene macrolides are very rare. Only two compounds without definite names were reported as the derivatives of 14-Membered RALs so far. The
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6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
metabolite, dihydroresorcylide (67), was also revealed to have wide spread occurrence in A. zeae (105
authors thinked that these two 13-membered macrolides (68, 69) (Table 1 and Fig. 8) isolated from the marine mangrove fungus Aigialus parvus BCC 5311 were possibly produced from air oxidation of aigialomycin A and hypothemycin, respectively. Possible mechanism for the production of 68 is
AC C
1 2 3 4 5
proposed in Scheme 1. Rearrangement from a 14-membered to 13- membered macrolides could be explained by carbon migration of hemiacetal [142]. Scheme 1. Possible mechanisms for the production of 13-Membered benzenediol lactones
21
2.5 14-Membered benzenediol lactones
14-Membered benzenediol lactones constituted the largest group of BDLs including more than 100 substances, the majority of which belonged to RALs family. These included aigialomycins, caryospomycins,
cochliomycins,
hamigeromycins,
hypothemycins,
monocillins,
monordens,
neocosmosins, paecilomycins, pochonins, zeaenols and zearalenones etc, which were mainly obtained from fungal species of genera Aigialus, Caryospora, Cochliobolus, Hamigera, Hypomyces,
TE D
Monocillium, Humicola, Neocosmospora, Paecilomyces, Pochonia, Drechslera and Fusarium etc. In addition, only three natural 14-membered benzenediol lactones resembled the DALs. Aigialomycins
EP
Fig. 9. The structures of aigialomycins
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1 2 3 4 5 6 7 8 9 10 11 12
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SC
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
22
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
1
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Compounds of this type include 9 RALs, 70-78 (Table 1 and Fig. 9). They were mainly reported as the secondary metabolites of the genus Aigialus.
In the course of screening for novel bioactive compounds from microbial sources, five resorcylic macrolides, aigialomycins A-E (70-74), were isolated from the mangrove fungus, A. parvus BCC 5311, along with previously reported hypothemycin (95) (see in Fig. 13) in 2002 [143]. The structures and
EP
absolute configuration of 70-74 were elucidated by chemical conversions, detailed analysis of the NMR spectroscopic and mass data in conjunction with X-ray data obtained on hypothemycin [143]. Several years later, another six new nonaketide metabolites including aigialomycin F and G (75 and 76), which can be looked as distinct aigialomycin derivatives, were isolated from the same marine
AC C
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
mangrove fungus by the same group [144]. The stereochemistry of 75 and 76 was addressed by conversion to acetonide derivatives. The result that the same compound could be prepared by hydrogenation of 75 and reduction of 76 with NaBH4 revealed that 75 and 76 possessed the same relative stereochemistry. On the basis of these experimental data and by biogenetic correlation to 71, the absolute configurations of 75 and 76 were deduced to be 1'R, 2'S, 4'S, 5'S, 6' S, 10'S and 1'R, 2'S, 4'S, 5'S, 10'S, respectively. Compounds (70-75) displayed weak activity against Plasmodium falciparum K1, cytotoxicities against two cancer cells (KB, BC-1) and Vero cells (African green monkey kidney fibroblast), of which aigialomycin D (73) was the most potent (IC50 were 6.6, 3.0, 18 and 1.8 µg/mL, respectively) [143]. Additionally, 73 also exhibited kinase inhibitory activities [145, 146] (IC50: 6 µM for CDK1/5, 21 µM for CDK2, and 14 µM for GSK) although it did’ t belong to those resorcylic macrolides containing a cis-enone moiety, which are well known as one of the more promising groups of natural products that have recently emerged as new lead structures for kinase 23
ACCEPTED MANUSCRIPT[Benzenediol lactones] 1 2 3 4
inhibition. The result suggested that different RAL scaffolds might inhibit different kinases via various
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
The compounds of this class have been found from other fungi. 1', 2'-Epoxyaigialomycin D (77)
resulting in eight total syntheses [145, 147-153]. In addition, 73 has recently been shown to bind to Hsp90, but does not function as an indiscriminate ATP antagonist [154].
was first isolated from H. subiculosus in 2006 with other hypothemycin analogues [155]. The structure was established by analysis of NMR and MS data, and the relative configurations were assigned by
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NMR analyses (1H, 13C, HSQC, HMBC, and TOCSY) and performing X-ray crystallographic analysis. The analysis revealed that the structure of 77 was very similar to that of 73, which just bore an epoxide functionality between C-1' and C-2' instead of the trans-olefinic bond [155]. Aigialomycin D (73), isolated from the cultures of Fusarium sp. LN-10, an endophytic fungus originated from the leaves of Melia azedarach in 2011, was revealed to have significant toxicity toward brine shrimp larvae (76.7%
SC
at a concentration of 10 µg/mL) [156]. In 2012, compounds 71-73, 75 and 77, obtained from the mycelial solid culture of Paecilomyces sp. SC0924, were found to have weak activities against Peronophythora litchii in an assessment of antifungal activity by the well plate diffusion method [157].
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Recently, deoxy-aigialomycin C (78) was first reported as a natural product isolated from the sea anemone-derived fungus C. lunatus. Its relative and absolute configurations were confirmed using NOE experiments of its acetonide derivative and the CD exciton chirality method with its pdimethylaminobenzoyl derivative. It exhibited potent antifouling activity at nontoxic concentrations with the EC50 value of 22.5 µg/mL [158]. Previously, 78 was obtained as a new aigialomycin analogue along with epi-Aigialomycin D through the syntheses studies of aigialomycin D [154]. Caryospomycins
Fig. 10. The structures of caryospomycins
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22 23
mechanisms. Consequently, 73 has attracted considerable interest from the synthetic community,
24
Three compounds of this type, 79−81 (Table 1 and Fig. 10), possessed a rare structure in which a 1,2-dimethoxy-4-hydroxybenzene ring fused into the 14-membered macrolides. In 2007, our group
AC C
25 26 27 28 29 30 31 32 33 34 35 36 37
reported the isolation of caryospomycins A-C (79-81), as a result of the investigation of the metabolites with activities against plant parasite nematodes from the fresh-water fungus C. callicarpa YMF1.01026, which was initially isolated from a submerged woody substrate collected from a freshwater habitat in Yunnan Province, China. The chemical structures of 79 − 81 were determined through NMR spectroscopic analysis. The spectra data combined with 2D NMR experiments indicated 80 was a deacetonided derivative of 79, and 81 was an analogue of 80 but with a different oxidation state at C-6'. In this report, these compounds were demonstrated to be active in an in vitro microtiter plate assay and exhibited moderate killing activity against the nematode Bursaphelenchus xylophilus with the LC50 values of 103.1, 105.8, and 105.1 ppm, at 36 hr, respectively [159]. Cochliomycins Fig. 11. The structures of cochliomycins 24
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
1
The compounds of this class, 82−87 (Table 1 and Fig. 11), were only obtained from fungus C. lunatus.
Cochliomycins A-B (82-83), two with a rare natural acetonide group, and cochliomycin C (84), one with a 5-chloro-substituted lactone, were isolated from the culture broth of C. lunatus, a fungus
TE D
obtained from the gorgonian Dichotella gemmacea collected in the South China Sea [160]. Their structures were elucidated by extensive spectroscopic analysis including 1D NOE and 2D NOESY experiments and chemical conversions. The only difference between cochliomycin A and B was the position of acetonide group. The absolute configurations of 82 and 83 were further confirmed after treatment of zeaenol (155) with 2, 2-dimethoxypropane in the presence of p-toluenesulfonic acid
EP
(PTSA) resulted in a mixture of cochliomycin A and B. However, cochliomycin C initially published structure 84a, was later revised to 84, which was assigned as 4'S, 5'R, 6'S, 10'S, by the same authors [161]. Interestingly, a transetherification reaction that compound 83 in a solution of CDCl3 slowly can be rearranged to give 82 at room temperature indicated cochliomycin A can arise from cochliomycin B
AC C
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
via a transetherification reaction in which the ether migrated from O-4' to O-6' [160]. Recently, the reinvestigation of the secondary metabolites from the sea anemone-derived fungus C. lunatus (collected from Weizhou coral reef in the South China Sea) led to the isolation of three new 14-membered resorcylic acid lactones, cochliomycins D−F (85-87), and eight known analogues. Detailed analysis of the 1D and 2D NMR spectra established the same planar structures for 85-87. Their absolute configurations were established by the CD exciton chirality method and TDDFT ECD calculations. The result indicated that these compounds were diastereomers differing from each other by the absolute configurations of the 4', 5'-diol chiral centers [158]. In antifouling assays, compound 82, 85 and 87 exhibited potent antifouling activities against the larval settlement of the barnacle B. amphitrite at nontoxic concentrations, with EC50 values of 1.2, 17.3 and 6.67 µg/mL, respectively. Structure−activity relationships suggested that the enone and acetonide functionalities and hydroxy configurations may have obvious influence on antifouling activity. Additionally, only 82 was found to 25
ACCEPTED MANUSCRIPT[Benzenediol lactones] have moderate antibacterial activity against S. aureus with an inhibition zone of 11 mm in diameter at a concentration of 50 µg/mL [158]. Very recently, cochliomycin A was firstly synthesized by Nanda’s group from L-(t)-tartaric acid in 6.5% overall yields employing Keck allylation [162] and then was stereoselectively synthesized based on chiron approach by Wang et al. [163]. Cochliomycin B (83) and zeaenol (155) have been synthesized from natural chiral template ι-arabinose in overall yield of 4.8%, by
Takai
olefination,
Suzuki
coupling,
alkoxide-mediated
transesterification,
and
RCM
Hamigeromycins Fig. 12. The structures of hamigeromycins
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macrocyclization as the crucial steps [164].
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This group of 7 compounds 88− − 94 (Table 1 and Fig. 12) features a 1, 2- dimethoxy- 4hydroxybenzene ring and a 14-member macrocyclic lactone ring, which includes a 1'-2' trans double bond, a ketone and one or two hydroxys. These compounds were all isolated from Hamigera avellanea.
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10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
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1 2 3 4 5 6 7 8 9
Hamigeromycins A (88) and B (89) were first isolated from the soil fungus H. avellanea BCC
17816 together with radicicol (103) [142]. In a subsequent study, the same team got hamigeromycins C–G (90-94) by altering a liquid fermentation medium (PYGM). The structures and the stereochemistry of these compounds were deduced by analyses of the NMR spectroscopic and mass spectrometry data in combination with chemical means. It should be noted that 88, 90, 91 and 92 were stereoisomers differing from each other in the absolute configurations of the 4', 5'-diol moiety; while 93 and 94 were unusual 5'-keto-analogs, and they were 6'-epimers to each other. Besides, 89 were characterized by containing an oxygen bridge [165]. In a cytotoxicity assay, all compounds were inactive against cancer cell lines (KB, MCF-7, and NCI-H187) at a concentration of 50 mg/mL, whilst compounds 88 and 90 showed weak growth inhibition against Vero cells (African green monkey kidney fibroblasts) with IC50 values of 42 and 13 mg/mL, respectively. All compounds were inactive in an antimalarial activity assay against P. falciparum K1 at 10 mg/mL [165]. Recently, several synthestic 26
ACCEPTED MANUSCRIPT[Benzenediol lactones] pathways of 89 were accomplished [166, 167]. Hypothemycins Fig. 13. The structures of hypothemycins
Compounds in this type are some of the highly oxygenated analogues in the group of 14-membered resorcylic acid lactones. There are 8 compounds, 95−102, within this type (Table 1 and Fig. 13), mainly isolated from genus Hypomyces and Phoma.
As the best known compounds in this type, hypothemycin (95) was originally isolated from H. trichothecoides along with 7', 8'-dihydrohypothemycin (96), and later reisolated from the fungal
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fermentations of A. parvus [143], Coriolus Versicolor [168], H. subiculosis [155] and Phoma sp. [169]. The absolute configuration of 95 had been tentatively determined many times by different methods, which included X-ray analysis using anomalous dispersion of oxygen atoms [168], X-ray analysis of an aigialomycin C4-bromobenzoyl derivative chemically correlated to hypothemycin [143], single crystal X-ray analysis in combination with the new solid-state CD/TDDFT methodology [169], and
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stereospecific total synthesis of 95 [170-172]. Both 95 and 96 were active against the protozoan, Tetrahymena furgasoni and the plant pathogenic fungi Ustilago maydis and Botrytis allii [173, 174]. In addition, hypothemycin 95 also exhibited strong antimalarial activity in vitro (IC50=2.2µg/mL) [143] and could identify therapeutic targets in Trypanosoma brucei [175]. Additionally, detailed enzymatic
AC C
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
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SC
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1 2 3
and biochemical studies revealed that 95 inhibited a variety of kinases including MEK1/2 (Kd=17 nM and 38 nM), β-type platelet-derived growth factor receptor (PDGFRβ ) (Kd=900 nM), FMS-like tyrosine kinase-3 (FLT-3) (Kd=90 nM), vascular endothelial growth factor receptor 1 (VEGFR1) (Kd=70
nM)
and
(VEGFR2)
(Kd=10
nM)
at
low
nanomolar
levels,
and
including
extracellular-signal-regulated kinase (ERK) (Kd=8.4 mM) at low micromolar levels [143, 168, 176-177]. It also exhibited potent antitumor efficacy [178-180]. In 2013, Xu et al. [181] made an investigation on the antifungal activity of hypothemycin against P. litchii in vitro and in vivo. They found that 95 inhibited spore germination of P. litchii with the inhibition rate of 90% at 0.39 µg/mL, of 100% at 0.78 µg/mL, caused the ultrastructural modifications of P. litchii, especially the plasma membrane, mitochondria, and vacuoles, reduced decay and suppressed peel browning of postharvest litchi fruit inoculated with P. litchii [181]. Several other hypothemycin analogues were found in fungi as well. 5'-O-Methylhypothemycin (97) 27
ACCEPTED MANUSCRIPT[Benzenediol lactones] was isolated from a Phoma sp. with 95. The structure of 97 was elucidated by means of spectroscopic data analysis [169]. In 1999, L-783,277 (98) and its trans-isomer, L-783,290 (99) were both obtained from a Phoma sp. (ATCC 74403) which was isolated from fruitbody of Helvella acetabulum [182]. 98 found by researchers at Merck was reported to be a potent and irreversible inhibitor of MEK1 with an IC50 at 4 nM, weakly inhibit Lck, and has no activity on Raf, PKA, and PKC to a limited degree. Detailed analysis revealed the inhibition was ATP-competitive associated with the formation of a covalent adduct between the enzyme and the inhibitor. The latter compound (99) showed dramatically
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reduced inhibitory effect on MEK compared to 98 (IC50=300 nM). Three hypothemycin analogues (100-102) were isolated from the fungal strains H. subiculosus DSM 11931 and DSM 11932. The structures of these compounds were elucidated by spectroscopic methods, in combined with chemical conversion of the C-4 hydroxyl group of 100 to an O-methyl group and X-ray crystallographic analysis on a single crystal of 101. One of the analogues, 4-O-demethylhypothemycin (100) exhibited potent and selective cytotoxic activities against cell lines (COL829, HT29 and SKOV3 with IC50 values of Monordens and monocillins Fig. 14. The structures of monordens and monocillins
SC
0.038, 0.10 and 1.8 µM, respectively) with a BRAF mutation [155].
AC C
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
17 18
This subgroup of 14-membered benzenediol lactones with 20 members, (103-119) (Table 1 and 28
ACCEPTED MANUSCRIPT[Benzenediol lactones] Fig. 14), were always isolated together from Humicola sp. Among them, monordens are structurally characterized by a chlorine substitution on the aromatic ring. Monocillins were first isolated from M. nordinii except compound monocillin II glycoside (115). The first 14-membered resorcylic lactone, monorden (103), (also known as monorden A or radicicol), was originally isolated as a potent tranquilizer from Monosporium bonorden in a soil sample collected in the Belgian Congo in 1953 [183]. After ten years, the same molecule was independently obtained from the culture filtrate of Neonectria radicicolas (anam. Cylindrocarpon destructans) (syn.
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C. radicicola) and was named radicicol [184]. With the establishment of its three chiral centers by X-ray crystal structure in 1987, it was figured out that the initial structure proposed for monorden was incorrect, thus leading to the common acceptance of radicicol as the name of this molecule [185, 186]. In 1992, Lett and Lampilas reported the first total synthesis of radicicol, which confirmed its absolute configurations in three stereocenters [187-189]. The biosyntheses of radicicol in Chaetomium chiversii
SC
and Pochonia chlamydosporia have been studied [190-192]. Later, radicicol has been found to widely distribute in diverse fungal species, including C. chiversii [193], Colletotrichum graminicola [194], Humicola sp. FO-4910 & FO-2942 [195, 196], Neophaeosphaeria quadriseptata [193, 197], Paecilomyces sp. SC0924 [157], P. chlamydosporia var. catenulatum (syn. Diheterospora
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chlamydosporias; Verticillium chlamydosporium) [198], P. luteo-aurantium [199] etc. It was also found to have antifungal activities against Neurospora sitophila, Giberella zeae [199] and A. flavus (MIC > 28 mg/mL) [200], antimalarial activity (with in vivo efficacy) [195], the inhibition of various signal transduction products such as p60v-src, p60c-src and p53/56lyn [201-203], inhibition of HIV-1 Tat transactivation (IC50 =0.027 µM) [204], inhibition of human breast cancer [205] and inhibition in vitro of heat shock protein 90 (Hsp90) (IC50=20 nM) [206-208]. Of them, the inhibition of Hsp90 attracted much attention of many researchers. Further study indicated 103 inhibited the ATPase activity
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of Hsp90 via competitive binding to the N-terminal ADP/ATP binding pocket with nanomolar affinity [207]. However, due to the highly sensitive functionalities of 103, including a Michael acceptor and an epoxide, both of which were readily metabolized, it was inctive to Hsp90 in vivo [209, 210]. Monorden B (tetrahydromonorden) (104) was originally reported as a synthetic compound but later was shown to be secondary metabolites of the fungus Humicola sp. FO-2942, which was
EP
originally discovered as a producing fungus of amidepsines, inhibitors of diacylglycerol acyltransferase (DGAT), by UV spectrum-guided purification [196]. Along with 104, monoden and three new analogues, monordens C to E (105-107) were also isolated from the same fungus [196]. Based on spectroscopic evidence mainly by NMR analysis, the structures of compounds (105-107) were
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
elucidated. The result showed that 105 was 5', 6'-dihydromonorden A, that 106 and 104 lacked the epoxide moiety of 105 and 103, instead by transenone [196, 211]. All monordens (103-107) caused the cell cycle arrest at G1 and G2/M phases in Jurkat cells at a higher concentration of 30 µM. But among them, only monordens A and E (113, 117) showed antifungal activities against A. niger with IC50 values of 12 and 70 µM, respectively [196]. Furthermore, monordens D (106) was found to inhibit Herpes Simplex Virus (HSV) and be antiparasitic against parasitic protozoan Eimeria tenella [212]. Monocillins were closely related to monorden in the aspects of biogenetic derivation, structure and bioactivity. Monocillins I~V (108-112) were first isolated as co-metabolites of monorden (103) from the fungus M. nordinii, a destructive mycoparasite of pine stem rusts in North America in 1980. Among them, only monorden (103) and monocillin I (108) were detected to have significant antifungal activities (MICs = 10-25 mg/mL) against P. debaryanum and weak activities against Rhizoctonia solani (MICs = 100-200 mg/mL) [213]. Seven years later, these metabolites were re-isolated with two 29
ACCEPTED MANUSCRIPT[Benzenediol lactones] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
new structurally related compounds, namely nordinone (113) and nordinonediol (114), from the same
43 44
moderate activities in the memory T cell model of HIV-1 latency (EC50 = 9.1 and 24.9 µM,
fungi [214]. The structures of 108-112 were all identified based on 1H and
13
C-NMR techniques and
mass spectra while that of 113 was confirmed by its direct conversion into radicicol [186, 214]. Structurally, monocillins V, III, II and IV (112, 110, 109 and 111) corresponded to 13-unchlorinated monordens B, C, D and E (104-107), respectively. In recent decades, the monocillins were usually encountered from diverse fungal species. Monocillin II and III (109, 110) and a monocillin II glycoside (115) were isolated from P. chlamydosporia var. catenulate [212]. Monocillins I (108) was separately
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isolated from N. quadriseptata (Basionym: Paraphaeosphaeria quadriseptata) occurring in the rhizosphere of the Christmas cactus Opuntia leptocaulis, and C. chiversii endophytic on Mormon tea Ephedra fasciculate [193, 197]. Monocillin IV (111) was reported from H. fuscoatra [200] and Penicillium sp. [204] together with 103. 111 displayed antimicrobial activity against the A. flavus (MIC = 56 mg/mL) and inhibitory activity on HIV-1 Tat transactivation (IC50 = 5 µM) [204]. Both monocillin
SC
I and II (108, 109) exhibited selective cytotoxicities against the human cancer cell lines MCF-7 and NCI-H460 (IC50=0.98 and 0.62 mM, respectively), SF-268, and MIA Pa Ca-2, MDAMB-231 [197, 205]. In 2009, 108-110 were reported as bioactive secondary metabolites from C. graminicola (Holomorph: Glomerella graminicola), which displayed significant antifungal activities against A.
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flavus and F. verticillioides in conventional paper disc assay [194]. In the same year, 108-111 were found from P. chlamydosporia TF-0480, and the former three (108-110) and 103 showed WNT-5A expression inhibitory activities with the IC50 values of 1.93, 7.36, 17.62 and 0.19, respectively [216]. It was also noteworthy that monocillin I was well-known for its potent inhibitory activity against Hsp90 as radicicol (103) did [193]. Moreover, monocillin I (108) displayed in vitro activity against the stalkand ear-rot pathogen S. maydis [194]. As expected, the biosyntheses of monocillin I (108) and monocillin II (109) have been proven to use a similar pathway although there are structural variations
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that have been attributed to different oxidation and reduction patterns during the hrPKS step and putative post-PKS enzymatic modifications (e.g. epoxidation and halogenation) [13, 191]. Tichkowsky and Lett reported the total synthesis of 108 and 103 via Miyaura-Suzuki couplings in 2002 [215]. A new monorden analog, monorden analogue-1 (116), along with two known monorden (103) and monocillin IV (111), was isolated from H. fuscoatra NRRL 22980. In this paper, the authors only 13
C-NMR, 2D-NMR, and mass
EP
established the planar structure of 116 after analysis of 1H NMR,
spectral data [200]. In 2009, Shinonaga and co-works reported the reisolation of 116 from P. chlamydosporia var. chlamydosporia and its WNT-5A expression inhibitory activities. Here, the
AC C
relative stereochemistry of 116 was elucidated to be 3α-methyl and 5α-hydroxyl based on 1H-1H coupling constants and NOESY data [216]. More recently, three new radicicol analogues, radicicols B-D (117-119), with four known
compounds radicicol and pochonins B, C, and N, were obtained from a marine-derived fungus H. fuscoatra (UCSC strain no. 108111A) via a bioassay-guided isolation process [217]. The extract of this species was shown to reactivate latent HIV-1 expression in an in vitro model of central memory CD4+ T cells. In this report, the structures of 117-119 were determined on the basis of the molecular formulas and NMR properties of the known compounds. The C-2 stereochemistry of 117-119 was all proposed to be analogous to that of radicicol (103). However, the relative configurations of the secondary alcohols of 118 and 119 were not assigned by NOESY correlation spectroscopy, due to the flexible skeleton lacking α, β, γ, δ-unsaturated ketone functionalities. Compounds 103 and 117 exhibited respectively), while 118 and 119 were inactive, indicating that the epoxide functionality is not required 30
ACCEPTED MANUSCRIPT[Benzenediol lactones] Michael acceptor functionality, something the inactive compounds 118 and 119 do not possess. Neocosmosins
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Fig. 15. The structures of neocosmosins
In 2013, bioassay-guided fractionation of a fungus Neocosmospora sp. (UM-031509) led to the isolation of three new resorcylic acid lactones, named neocosmosins A (120), B (121), and C (122),
SC
(Fig. 15) along with three known RALs (103, 109 and 111). The structures of new compounds were established on the basis of extensive 1D and 2D-NMR spectroscopic analysis, and mass spectrometric (ESIMS) data in conjunction with X-ray data obtained on 111. In the binding assays in vitro, neocosmosins C showed good binding affinity for the human opioid receptors, which selectively
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inhibited 54.9% of the specific binding of [3H]-enkephalin to CHO-K1 cell membranes expressing human δ-opioid receptors at the concentration of 10 µM (IC50 value of 14.82 µM). Meanwhile, known compounds 103 and 109 also showed potent binding affinities at the µ-opioid receptor (63.5% and 84.9%, respectively). The authors declared that this was the first report on resorcylic acid lactone derivatives with strong affinities for human opioid receptors [218]. Paecilomycins
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Fig. 16. The structures of paecilomycins
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5 6 7 8 9 10 11 12 13 14 15 16 17 18
for activation of HIV-1. Moreover, it was also noted that the active compounds (103, 117) all contain a
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1 2 3 4
31
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This group of 13 RALs, 123-135 (Table 1 and Fig. 16), are marked as the secondary metabolites of Paecilomyces sp. They are usually highly oxygenated analogues possessing epoxy, hydroxyl, and other oxygen-containing groups on the macrolide ring.
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
During the investigation on the secondary metabolites of Paecilomyces sp. SC0924, Xu et al.
reported the isolation and identification of 13 new benzenediol lactones, named paecilomycins A-M (123-135), together with several known RALs (71-73, 77, 109, 159, 161, 181) from the mycelial solid culture of this fungus, successively [219-221]. Their structures (123-135) were elucidated by extensive NMR analysis and chemical correlations in conjunction with X-ray analysis of paecilomycins A and J. Furthermore, the absolute configurations of paecilomycins J-M (132-135) were assigned by Time-Dependent Density-Functional Theory (TDDFT) calculations of their electronic circular dichroism (CD) spectra after their isolation. Paecilomycins E (127) and F (128) were reversedly assigned in the original isolation report then revised [222] while 135, initially assigned structure 135a, was also revised to 135 [220, 223]. Among them, paecilomycin C and D (125 and 126) having a dihydroisobenzofuranone ring and a polyhydroxylated linear C-10 side chain, which were believed to be biogenetically derived from common macrocyclic RALs through intramolecular SN2-type 32
ACCEPTED MANUSCRIPT[Benzenediol lactones] nucleophilic substitution, were unusual for RALs [144]. It was also very rare in natural RALs that 124 contained an oxygen bridge between C-1' and C-5' to form a pyran ring and 132-135 each contained an ether linkage between C-2' and C-5' to form a tetrahydrofuran (THF) ring. In the assay against the P. falciparum, paecilomycin E (127) displayed antiplasmodial activity against P. falciparum line 3D7 with IC50 value of 20.0 nM, while paecilomycin A, B, F (123, 124, 128) showed moderate activities with IC50 values of 0.78, 3.8, 1.1 µM, respectively. Additionally, 127 and 128 showed moderate activities against P. falciparum line Dd2 with IC50 values of 8.8, 1.7 µM, respectively. Paecilomycin M (135)
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exhibited weak antifungal activity against P. litchii [157, 181, 221]. In 2012, the stereoselective total synthesis of 128 and the asymmetric total synthesis of 127 were achieved by Srihari [224] and Nanda group [162], respectively. More recently, paecilomycin F (128) was identified from a sea anemone-derived fungus C. lunatus [158]. However, no activity was reported in this paper. Pochonins Fig. 17. The structures of pochonins
14 15 16 17 18 19 20 21 22 23 24 25
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1 2 3 4 5 6 7 8 9 10 11 12 13
These RALs include 16 pochonins, 136-150 (Table 1 and Fig. 17) and 106 (Fig. 14) which were
obtained from P. chlamydosporia var. catenulata strains P0297 and TF-0480 by two different research groups. The entire family of pochonins shared a common structural motif of a 14-membered macrocyclic resorcylic acid lactone core, which was analogous to radicicol (103) except for pochonins F and J (140 and 144) chlorinated at C-5 of the aromatic ring [212, 216]. Differed from the other pochonins, 140 and 144 demonstrated more semblances to the aigialomycin and hypothemycin families of natural products, partly, due to the lack of C-13 chlorination [143, 173]. Interestingly, many pochonins were found to inhibit Hsp90, which may be due to the same pharmacophore as radicicol. Pochonins A-F (136-138, 106, 139-140) were isolated from the strain P. chlamydosporia var. catenulata P0297 [212] while pochonins E-P (139-150) were obtained from P. chlamydosporia var. chlamydosporia TF-0480 [216, 225]. Their structures were elucidated by means of a combination of 33
ACCEPTED MANUSCRIPT[Benzenediol lactones] 1D and 2D spectroscopic techniques. The stereochemistry of the C-7' chlorine in pochonin C (138) had not been firmly established until confirmation by total syntheses [170, 226-227]. While the stereochemistry of the C-6' hydroxyl group in pochonin E and F (139, 140) was first assigned as S-stereochemistry by Shinonaga’s group [225], but later revised R by comparison between the reported proton NMR data of the natural products and the synthetic compounds [228]. An efficient synthesis of ent- pochonin J has been achieved by Martinez-Solorio et al., but does not match the spectroscopic data of pochonin J (144) as initially reported. Further attempts at the structural verification of pochonin J are
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ongoing [229]. Interestingly, we find pochonin D has the same chemical structure as monorden D (106). In the HSV1 (Herpes Simplex Virus 1) replication assay, all the pochonins with epoxide moieties or allyl alcohol moieties (e.g., 136, 137, 139, 140) exhibited bioactivities in the low µM range. Pochonin D (106) which contains a double bond instead of the epoxide ring, showed only cytostatic effects. The authors presumed that the chlorine substituent was probably not essential for the antiviral activity
SC
because monocillin (110) without halogenation also showed inhibitory activity against HSV1 in the nM range. The antiparasitic activities of 136-140 and 106 were tested against Neospora caninum and Eimeria tenella. The result indicated that all the test compounds was not susceptible to N. caninum, but the partly hydrogenated pochonins containing an epoxide function showed moderate activities against
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E. tenella. Among these, pochonin A (136) exhibited the best selectivity toward the parasite. In searching for an inhibitor of WNT-5A expression, radicicol (103) showed the strongest WNT-5A inhibitory activity of the tested samples, however, it also showed relatively high cytotoxicity. The inhibitory activities of 141, 145 and 149 were 10-fold weaker than that of 103 while pochonins 142-144, 147-148 and 150 were practically inactive. However, compared with 103, compound 141 and 149 showed no cytotoxicity at concentrations above 100 µM. The data implied that the 4,5-epoxide or 4,5-E-olefin moieties present in 145 and 149, or 139 and 140, respectively, may be necessary for
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radicicol-type compounds designed to inhibit WNT-5A expression, but the chlorine atom at C-13 may decrease the toxicity against dermal papilla cells.
Besides the species P. chlamydosporia, recently, pochonin N (148) was found in the cultures of Fusarium sp. LN-10, an endophytic fungus originated from the leaves of Melia azedarach, and displayed significant growth inhibitory activity against the brine shrimp Artemia salina at a
EP
concentration of 10 µg/mL, with mortality rate of 82.8% [156]. Pochonins B-C and N (137-138, 148) were also identified from the extract of H. fuscoatra (UCSC strain no. 108111A) with 103. Among them, 137 and 138 showed moderate activities in the memory T cell model of HIV-1 latency [217]. Many pochonins have already been determined the inhibitory activities of Hsp90 by severeal
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43
authors because they are structurally related to radicicol [210, 228]. The result found only pochonin A, D, E and F (136, 106, 139, 140) were active to Hsp90. Of pochonins tested, the best strong compound pochonin D had an affinity for Hsp90 (IC50 = 80 nM), which was 4-fold less than radicicol (IC50 = 20 nM). The epoxide derivative, 136 was also found to be a good inhibitor of Hsp90 (IC50 = 90 nM) whereas the 7′, 8′-diol analog was inactive [19]. The data suggested that neither an epoxide ring nor the dienone was critical for Hsp90 binding. The study on action mechanism indicated these compounds had very different conformations in solution which could rationalize their different biological activities. Interestingly, Moulin E. and his team have exemplified how macrocycle functionalization could not only direct kinase selectivity, but also selectivity between target classes [145, 230]. Zeaenols Fig. 18. The structures of zeaenols
34
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Natural resorcylic lactones of fungal origin from the zeaneols group, 151-158, (Table 1 and Fig. 18) are mainly spread in D. portulacae, C. lunatus, and other unidentified fungus. They exhibit a wide range of biological properties which include oestrogenic, antifungal, phytotoxic and anti-inflammatory activity.
LL-Z1640-1 to 4 (151-154) were first isolated from an unidentified fungus (Lederle Culture 21640) in 1978 [231]. In this paper, the authors found these compounds no particularly interesting activities. They emphasized that these compounds were devoid of anabolic and estrogen-like activity even if they
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were structurally related to zearalenone, a well-known oestrogen hormones. Here, the information about the double bond in 154 was not given. In the same year, Japanese scientists Yuki et al. reported the isolation and structure elucidation of a new metabolite zeaenol (155) from C. lunata grown on potato and (or) Czapek-Dox medium during the chemical studies on aversion-antagonism [232]. In this paper zeaenol was not only confirmed to have the same planar structure to 154 but also the authors
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further revealed that the stereochemistry of the double bond at C-7'-C-8' was trans-configuration while the C-6 hydroxyl had α-configuration orientation. Later, some researchers held the opinion that 154 and 155 were the same compound [233]. In 1992, a paper published the fact that LL-Z1640-1 (151) and zeanol (the same structure as that of 155) cooccured in Drechslera, inhibited plant growth [234].
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
Additionally, we found that compounds L-783,278 and L-783,279 reported from strains (MF6280, MF6293) during the course of screening for potent inhibitors of MEK kinase were 152 and 151, respectively, by comparing their physical and spectroscopic data [235]. Recently, total syntheses of 155 were accomplished by Jana and Nanda [162], Gao et al. [164] and Dakas et al. [236], respectively. In 1999, the capacity of several zearalenone derivatives (152, 155, 156 and 157) to inhibit
lipopolysaccharide
(LPS)-induced
cytokine
production
in
phorbol
12-myristate-13-acetate
(PMA)-treated cultured myelomonocytic cells (U937) was revealed. They exhibited IC50 values of 6 nM, 10 mM, 500 nM and 5 µM, respectively [233]. They were obtained from a 50 L fermentation of Xenova fungus 20416, C. lunatu and named 5Z-7-oxo-zeaenol (152), zeaenol (155), 7-oxo-zeaenol (156) as well as 5, 6-dihydo-5-methoxy-7-oxo-zeaenol (157), respectively. The first total synthesis of 152 was published by Tatsuta et al. [170] in 2001 followed by the Lett et al. [171, 172]. Structurally, we found that 5Z-7-oxo-zeaenol had the same structure as 152. Later, 152 was found to be an 35
ACCEPTED MANUSCRIPT[Benzenediol lactones] ATP-competitive potent and selective inhibitors of TAK1 (IC50=8.1 nmol/L) and ERK2 (IC50=8.0 nmol/L) [17, 237]. Since then, interest in these molecules was renewed. Many 152 analogs were surveyed their inhibitory activities against a variety of kinases and their SARs were presented [25]. With regard to the macrocyclic ring of these molecules, the cis-enone was essential for the activities and modification on the enone moiety or adjacent position (C4) may improve metabolic stability by summarizing the SAR of RALs’ inhibitory activity on kinases established so far. It was also noted that the diol moiety at C8-C9 contributed to the bioactivity, although the C9-OH was more important than
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the C8-OH. Moreover, in the case of the resorcylic ring: addition of N or O-functional group at C13 or C13-C14 fused bicyclic heterocycle can enhance both potency and PK properties [25].
Two new compounds, 15-O-desmethyl-(5Z)-7-oxozeaenol (158) and 7-epi-zeaenol, along with four known RALs (151, 152, 155, 156) were found in filamentous fungal extract of the Mycosynthetix library (MSX 63935; related to Phoma sp.) [15]. Noticeably, the author described 7-epi-zeaenol not a
SC
natural product which was produced by reduction of (5E)-7-oxozeaenol (156) with sodium borohydride. In a series of assays, 152 was the most potent representative of this class of compounds in both cytotoxicity assays against cancer cell lines (MCF-7, H460, SF268, HT-29, MDA-MB-435) and the NF-κB assay [15].
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In the recent studies, LL-Z1640-1 (151), LL-Z1640-2 (152), zeaenol (155), (5E)-7-oxo-Zeaenol (156), have also been found in the culture broth of C. lunatus (obtained from the gorgonian D. gemmacea) [158]. All the four compounds showed potent antifouling activity against the larval settlement of barnacle B. amphitrite (EC50 values of 5.3, 1.82, 1.2, 18.1 µg/mL, respectively). 151 showed moderate cytotoxicities against A549 and HepG2 tumor cell lines with IC50 values of 44.5 and 98.6 µM, respectively, while LL-Z1640-2 showed cytotoxicity against HCT-116 with an IC50 value of 3.24 µM. Among these compounds, only 152 exhibited promising antifungal activity against Pestalotia
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calabae (MIC = 0.39 µM) and excellent agricultural fungicidal activities against Plasmopara viticola and P. infestans on the whole-plant assay [158, 160, 161]. Additionally, it was also noted that 151 found in Paecilomyces sp. showed weak activity against P. litchii [157]. Zearalenone and its structurally related conpounds
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Fig. 19. The structures of zearalenone and its structurally related conpounds
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
36
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The compounds (159-181) (Table 1 and Fig. 19) of this group were usually reported as the metabolites of zearalenone in fungi, plants and mammalian systems, as well as the pharmacokinetics. These compounds shared the same carbon backbone close spatial similarity to 17-estradiol [238]. A few review papers have been given on the occurrence, structures and pharmacokinetics of a part of this
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
group [239-241] before. Here we summarize and update the information to date. Compound 159 described as 6-(10-hydroxy-6-oxotrans-1-undecenyl)-ß- resorcyclic acid lactone,
was first isolated from the mycelium of the fungus Gibberella zeae (Syn. F. graminearum) growing as a mould on corn by Stob et al. in 1962 [242], and its chemical structure disclosed by Urry et al, who also coined the name zearalenone (ZEA, ZEN, 159), by combining elements of its predominant occurrence (‘zea’ for maize) with characteristic structural features (‘RAL’ for the resorcylic acid lactone structure, ‘en’ for the olefinic double bond, and ‘one’ for the keto group) [243]. Zearalenone has attracted much attention since it was found. So far, it has been shown to have estrogenicity [244], teratogenicity [245], mutagenicity [246], genotoxicity [247-249], cytotoxicity [248], immunotoxicity [250-253] and hepatonephrotoxicity [254, 255], and to be an enhancer of lipid peroxidation [256] and a cattle-growth stimulant [257, 258] etc. Additionally, it was noted that zearalenone is also one of the most worldwide distributed mycotoxins [259]. The major mycotoxicity of 159 was attributed to its 37
ACCEPTED MANUSCRIPT[Benzenediol lactones] estrogenic effects on genital organs [260] and on reproductive performance [261, 262]. The toxicity to the reproductive system resulted in uterine enlargement, alterations to the reproductive tract, reduced litter size, increased embryolethal resorption, decreased fertility and changes in progesterone and estradiol serum levels in animals [263-267]. Zearalenone (159) is the only member of this family of which the biosynthesis has been genetically characterized, with two reports detailing the identification of the biosynthetic gene cluster from G. zeae [268, 269]. For zearalenone, more than ten synthetic strategies have been designed after its first total synthesis was published in 1967 [270].
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Following the isolation of zearalenone, Bolliger and Tamm reported the identification of four zearalenone-related fungal metabolites in F. graminearum cultures, i.e. 13-formyl-zearalenone (160), 5, 6-dehydro-zearalenone (161), and the two stereoisomers of 5-hydroxy-zearalenone (162a, 162b) in 1972 [271]. The formation of 5-hydroxy-zearalenone (162) was later confirmed by several groups [272-274], and further metabolites were disclosed, i.e. 5-hydroxy-zearalenol (163) [275], the epimers
SC
of 10-hydroxy-zearalenone (164a, 164b) [276].
In 1985, several closely related compounds were detected in fungal incubations, i.e. zearalenone (159), α-zearalenol (165a), β-zearalenol (165b), zearalanone (166), α-zearalanol (also named zeranol) (167a), ß-zearalanol (also named taleranol) (167b), cis-zearalenone (168), as well as the epimers of
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cis-zearalanol (169a, 169b) [277]. Early studies on the metabolism of zearalenone have also disclosed the formation of reductive metabolites, in particular stereoisomers of zearalenol (165a, 165b) [249, 278-281]. Among them, α-Zearalenol (167a) exhibited an even higher estrogenic activity than β-zearalanol (taleranol) (167b) and zearalenone (159) suggesting that the orientation of the hydroxyl group at the aliphatic ring may have a pronounced effect on the oestrogenic activity [274, 282].
α-Zearalanol (167a), also named zeranol, was used as a growth promoter in livestock under the product name Ralgro® [283] because of its high oestrogenic activity. In 2003, a study has demonstrated that the
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catechol metabolites of the 167a had a DNA-damaging potential [247]. Recent investigation indicated that 159, 167a and 167b can interfere with various enzymes involved in steroid metabolism [284, 285]. A series of important papers on zearalenone (159) transformation by fungi and actinomycetes have been published [286, 291, 292,]. Two new transformation products, 2, 4-dimethoxyzearalenone (168) and 2-methoxyzearalenone (171), were obtained from 159 by the cultures of the fungus
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Cunninghamella bainieri. They were found not bind to rat oestrogen receptor, indicating a loss of oestrogenicity [286]. A considerable amount of 159 was found to be present as zearalenone14-β-D-glucopyranoside (172) [287] or zearalenone -14- O-sulfate (173) in Fusarium cultures [288, 289]. In 1988, Engelhardt et al. found that 159 can be transformed to 172 by maize cell suspension
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
cultures [287]. 172 can also be produced from 159 by several fungi and actinomycetes such as Rhizopus sp. [291], Mucor bainieri, and Thamnidium elegans etc. [292]. Taking together, there were two sites for glycosylation present in 159, but conjugation in position 14 was strongly favored compared to position 16 [293]. Zearalenone-14-sulfate (formerly known as zearalenone-4-sulfate) (173) was first isolated by
Plasencia and Mirocha from rice inoculated with F. graminearum [288]. El-Sharkawy et al. reported the conversion of zearalenone into 173 by many microorganisms [294] and Berthiller et al. identified zearalenone-14-sulfate as phase II metabolite of zearalenone in the model plant Arabidopsis thaliana [295]. The conjugate most likely retained biological properties of the mycotoxin, since the sulfate moiety was easily cleaved under acidic conditions and in rats [294]. Therefore, 173 was included in analytical methods for the determination of free and masked mycotoxins during the last years [296-298]. 38
ACCEPTED MANUSCRIPT[Benzenediol lactones] Recent decades, some new natural zearalenone derivatives were identificated. In 2008, 5'-hydroxyzearalenol (174) was isolated from the culture broth of a marine-derived fungus Fusarium sp. 05ABR26 with three known compounds (159, 162a and 165). The structure and relative stereochemistry of 174 were elucidated on the basis of spectroscopic data and single-crystal X-ray diffraction data. Of the antifungal and antimitotic activities tested, compound 159 displayed potent inhibitory activity against P. oryzae with a MIC value of 6.25 mg/mL, while compound 162a was much less active; however, 174 and 165 showed no obvious activity [299]. In the same year, two new
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derivatives, 8'-hydroxyzearalanone (175) and 2'-hydroxyzearalanol (176), were isolated from the marine-derived fungus Penicillium sp. along with four known zearalanone derivatives. The structures were elucidated by spectroscopic methods [300]. In 2010, a culture of F. graminearum has been reinvestigated using LC-DAD-MS and, in part, NMR spectroscopy. In addition to confirming most of the previously reported zearalenone metabolites (162a, 162b, 164a, 164b), several novel compounds
SC
were identified. Three of the metabolites were shown to have the structures of zearalenone -11, 12-oxide (177), zearalenone-11, 12-dihydrodiol (178) and 10-keto-zearalenone (179) [301]. As a novel compound, 5'-hydroxyzearalenone (180) and six known ß-resorcylic macrolides (15, 159, 161, 162, 165b and 174) were isolated from the seagrass-derived fungus Fusarium sp. PSU-ES73 in 2011. Their
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structures were established by analysis of spectral data. Among them only the known compound zearalenone (159) displayed weak antibacterial against S. aureus (MIC = 400 µM) and antifungal activities against C. neoformans (MIC = 50.26 µM) [40]. In 2010, trans-7', 8'-dehydrozearalenol (181), along with zearalenones (159 161), were isolated from the mycelial solid culture of Paecilomyces sp. SC0924. Their structures were established by spectroscopic methods and chemical means [220]. Structure-activity relationships for human estrogenic activity in zearalenone mycotoxins have been reported. The 6' functional group had the largest effect on estrogenicity. In both the zearalenone
TE D
series (trans double bond at 1', 2') and the zearalanone series (saturated double bond at 1' , 2') the order of estrogenicity for 6' substituents was α-OH
NH2≥ =O ≈ β-OH
β-OAc. Meanwhile, increased
flexibility in the macrocyclic lactone ring would be expected to favor tighter binding of a zearalenone analog to the estrogen receptor. Because saturation of the 1', 2' double bond increased flexibility of the macrolide ring, the order of estrogenicity for 1', 2' double bond was dihydro
trans
cis. This
EP
order of activity was observed for 6'-ketone derivatives, however, not observed in the present study for derivatives with other 6'-functional groups (α-OH, β-OH, β-OAc), in which case saturating the 1', 2' trans double bond resulted in a 5- to 8-fold reduction in estrogenicity. In addition, resorcinol OH groups contributed little to the binding of zearalenones to the human estrogen receptor. Placing a
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
hydroxyl group near the macrolide ring methyl group enhanced receptor binding, even though the hydroxyl was one carbon further away than in 17β-estradiol [238]. Other 14-membered resorcinylic acid lactones Fig. 20. The structures of other 14-membered resorcinylic acid lactones
39
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
1
Apart from the types as described above, there are some special 14-membered RALs, 182-185,
SC
(Table 1 and Fig. 20).
Radicicol A (87-250904-F1) (182) belongs to the subset of RALs bearing a cis-enone. 182 was first reported as a kinase inhibitor by researchers from Sandoz who identified this fungal metabolite during a screen for IL1ß inhibition [302]. The authors found that 182 accelerated the specific mRNA
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sequences including IL1ß’ s and inhibited tyrosine [233, 302-304]. As a natural product, radicicol A was also isolated from C. lunatus [233] and H. avellanea [142]. In 2005, Marzinzik and co-workers accomplished the first synthesis of 182 [305]. Later, concise syntheses and total syntheses of 182 were also reported by Dakas et al. [304] and Hofmann et al. [24], respectively. In 1998, using high throughput screening of microbial broths (Curvularia sp.), Williams et al identified Ro 09-2210 (183) as a selective inhibitor of MAP kinase kinase 1 (MEK1) with an IC50 at 59 nM. Interestingly, Ro 09-2210 was a highly selective MEK1 inhibitor although it only showed marginal inhibition on other
TE D
kinases such as PKC, PhK, PKA, ZAP-70, and Lck [306].
Queenslandon (184) characterized by a dihydroxyacetone subunit and a highly oxidized benzoic acid, was isolated from the strain C. queenslandicum IFM51121, which was isolated from a soil sample collected in Egypt, and deposited in the collection of Research Center for Pathogenic Fungi and Microbial Toxicoses, Chiba University, Japan. The structure, initially elucidated 184a on the basis of
EP
optical spectroscopy(IR), electrospray (ESI-MS) and high-resolution electron impact mass spectrometry (HREI-MS), one and two dimensional NMR spectroscopy (1H, 13C, DEPT, COSY, HMQC, HMBC, NOESY and TOCSY) [307], was later revised to 184 on the basis of the synthetic studies [308]. It showed distinct activity against fungi including A. nidulans IFM 5369, A. alternata
AC C
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
IFM 41348, P. variotii IFM 40913, P. chrysogenum IFM 40614, A. flavus IFM 41934, A. fumigatus IFM 41088, A. terreus IFM 40851, and A. niger IFM 5368, but not against bacteria such as Micrococcus luteus IFM2066 and B. subtilis PCI 219 [308]. In 2012, in the course of screening for environmentally benign secondary metabolites regulating
the motility and viability of zoospores of P. viticola, cryptosporiopsin A (185) together with hydroxypropan-2', 3'-diol orsellinate, pentapeptide were isolated from the culture of Cryptosporiopsis sp., an endophytic fungus from leaves and branches of Zanthoxylum leprieurii (Rutaceae) [309]. The structures of 185 were elucidated on the basis of spectroscopic analysis and comparison of its spectrometric data with that of ponchonin D. It was noteworthy that resorcylic acid monomethyl ethers with a non-chelated OH group as in 185 were very rare. Cryptosporiopsin A exhibited motility inhibitory and lytic activities against zoospores of the grapevine downy mildew pathogen P. viticola (10µg/mL), inhibitory activity against mycelial growth of two other peronosporomycete 40
ACCEPTED MANUSCRIPT[Benzenediol lactones] Rhizoctonia solani, and displayed cytotoxic activity to brine shrimp larvae [309]. 14-membered dihydroxyphenylacetic acid lactones
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Fig. 21. The structures of 14-membered dihydroxyphenylacetic acid lactones
So far only three compounds, 186-188 (Table 1 and Fig. 21), belong to 14-membered DALs. Two naturally derived 14-membered macrolactones, y5-02-B and y5-02-C (186, 187), have appeared in
SC
a Japanese patent as lead structure concerning the inhibition of neuropeptide Y receptor for anti-obesity programs [310], however the more detailed information could not be obtained. In 2008, the chemical investigation of the cytotoxic extract of the marine-derived fungus Curvularia sp. (strain no. 768), isolated from the red alga A. spicifera, yielded the novel macrolide apralactone A (188). The structure was elucidated by interpretation of its spectroscopic data (1D and 2D NMR, CD, MS, UV and IR). The compound was evaluated for the cytotoxic activity towards a panel of up to 36 human tumor cells and showed concentration-dependent cytotoxicities with a mean IC50 value of 9.87 µM [128]. 2.5 Novel benzenediol lactones
Fig. 22. The structures of novel benzenediol lactones
17 18 19 20 21 22 23 24 25 26 27 28
AC C
EP
TE D
5 6 7 8 9 10 11 12 13 14 15 16
phytopathogens, Pythium ultimum, Aphanomyces cochlioides and a basidiomycetous fungus
M AN U
1 2 3 4
Menisporopsin A (189) (Table 1 and Fig. 22), a novel BDL, was isolated from a cell extract of
the seed fungus Menisporopsis theobromae. The structure of 189 was elucidated on the basis of spectroscopic analysis and chemical transformations, with the absolute configuration established by application of the modified Mosher’s method and by using chiral HPLC. Menisporopsin A possessed an unprecedented residue, 2, 4-dihydroxy-6-(2, 4-dihydroxy-n-pentyl) benzoic acid. This compound exhibited antimalarial activity with an IC50 value of 4.0 µg/mL, and antimycobacterial activity with a MIC value of 50 µg/mL [311]. 3. Conclusions The review summarized in the above sections illustrates the isolation, structural determination, biogenetic studies, biological evaluation, and synthesis of eight-, ten-, twelve-, thirteen-, fourteen-membered BDL compounds. These natural products have attracted much attention from 41
ACCEPTED MANUSCRIPT[Benzenediol lactones] biologists and chemists because they were isolated from a variety of fungi and possessed fascinating molecular architectures and attractive biological activities. To date, about 190 BDLs with broad-spectrum bioactivities have been identified from the fungi. The members of BDL family are still expanding and the wide-range bioactivities of BDLs are still explored extensively. For this kind of compounds, general biosynthetic pathways have been defined; however, significant pathway branching for individals is still needed to explore. From a chemical synthesis perspective, while several elegant approaches to important BDLs have been reported, synthesizing such compounds through concise and
RI PT
modular routes which can be used to extend the diversity of this family remains challenging. From a therapeutic perspective, these fungal lactones may serve as promising lead structures for the development of new therapeutics for the treatment of cancer progression and metastasis as well as chronic fibrotic diseases. However, the preclinical development of some promising results from in vitro studies was hindered due to poor stability in blood plasma and liver microsomes, which need an
SC
extensive medicinal chemistry effort to improve its pharmacokinetic properties. Meanwhile, demand for BDLs in medicinal lead identification and in understanding mechanism of activities will lead to continuing the research in this field. Abbreviations Benzenediol lactones
RALs
Resorcylic acid lactones
M AN U
BDLs:
Dihydroxyphenylacetic acid lactones
IUPAC
International union of pure and applied chemistry
iPKSs
Iterative polyketide synthases
nrPKS
Nonreducing iterative polyketide synthases
Hsp90
Heat shock protein 90
NMR
Nuclear magnetic resonace
cAMP-PDE EGF PDGFR ATP HPLC ESIMS CD
Cyclic adenosine 3', 5'-monophosphate phosphodiesterase
50% inhibitory concentration
Extracellular-signal-regulated kinase Beta-type platelet-derived growth factor receptor
Adenosine Triphosphate
EP
IC50
TE D
DALs
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
High performance liquid chromatography
Electrospray ionization mass spectrometry
Circular dichroism
TDDFT
Time-dependent density functional theory
NOESY
Nuclear overhauser effect spectroscopy
MDR
Multidrug-resistant
NCI
Nonsmall cell lung
MTPA
(−)-α-methoxy-α-(trifluoromethyl) phenylacetyl
PL
Pancreatic lipase
MR
Mineralocorticoid receptor
TGF-b
Transforming growth factor-β
A549
Human lung adenocarcinoma epithelial cell line
HeLa
Human Henrietta Lacks cervical cancer cell line
Ehrlich
Mice Ehrlich ascites carcinoma cell line;
MCF-7
Human breast adenocarcinoma cell line 42
ACCEPTED MANUSCRIPT[Benzenediol lactones] Inducible nitric-oxide synthase
AChE
Acetylcholinesterase
FBF
fermented B. formosana
ED50
50% effective dose, ED50
DNA
Deoxyribonucleic acid
COSY
Correlation spectroscopy
HMBC
Heteronuclear multiple bond coherence
HMQC
Heteronuclear multiple quantum correlation Human prostate cancer
Huh
Human hepatocarcinoma
SGC
Human gastric carcinoma
SW1990
Human pancreatic cancer
PYGM
A Liquid Fermentation Medium
PDGFRβ
β-type platelet-derived growth factor receptor
MEK
Methyl ethyl ketone
FLT-3
FMS-like tyrosine kinase-3
VEGFR
Vascular endothelial growth factor receptor
ERK
Extracellular-signal-regulated kinase
PKA
Proteinkinase A
PKC
Proteinkinase C
MIC
Minimum inhibitory concentration
HIV
Human immunodeficiency virus
DGAT
Diacylglycerol acyltransferase
UV
Ultraviolet spectroscopy
M AN U
TE D
Herpes simplex virus
THF
tetrahydrofuran
SAR
Structure activity relationship
TNF-α
Tumour necrosis factor-alpha
ZAL
AC C
IL
Zearalenone
EP
ZEA ZEN
RNA
10 11
SC
Du1
HSV
1 2 3 4 5 6 7 8 9
RI PT
iNOS
Zearalenone Zearalanol
Interleukin Ribonucleic Acid
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China
(20762015, 31270091) and the Scientific Research Foundation of Southwest University to Dr. Jinyan Dong (swu109046). References
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· · · ·
Highlights The numerous biological activities of benzenediol lactones have been discussed. The chemical scaffolds of benzenediol lactones have been discussed. The natural sources of benzenediol lactones have been discussed. The structure activity relationships (SAR) of benzenediol lactones for different activities have been discussed in this review.
S0223-5234(14)01111-8
DOI:
10.1016/j.ejmech.2014.11.067
Reference:
EJMECH 7562
To appear in:
European Journal of Medicinal Chemistry
Received Date: 29 July 2014 Revised Date:
4 November 2014
Accepted Date: 26 November 2014
Please cite this article as: W. Shen, H. Mao, Q. Huang, J. Dong, Benzenediol lactones: a class of fungal metabolites with diverse structural features and biological activities, European Journal of Medicinal Chemistry (2015), doi: 10.1016/j.ejmech.2014.11.067. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
TITLE PAGE
2
Benzenediol lactones: a class of fungal metabolites with
3
diverse structural features and biological activities
4
Weiyun Shen, Hongqiang Mao, Qian Huang & Jinyan Dong*
Key Laboratory of Eco-environments in Three Gorges Reservoir Region (Ministry of Education), School of Life Science, Southwest University, Chongqing 400715, People's Republic of China
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*E-mail: [email protected], Tel: 86-023-68252400
Abstract: Benzenediol lactones are a structurally variable family of fungal polyketide metabolites possessing a macrolide core structure fused into a resorcinol aromatic ring. These compounds are
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widespread in fungi mainly in the genera such as Aigialus, Cochliobolus, Curvularia, Fusarium, Humicola, Lasiodiplodia, Penicillium and Pochonia etc. Most of these fungal metabolites were reported to possess several interesting biological activities, such as cytotoxicities, nematicidal properties, inhibition of various kinases, receptor agonists, anti-inflammatory activities, heat shock response and immune system modulatory activities etc. This review summarizes the research on the isolation, structure elucidation, and biological activities of the benzenediol lactones, along with some available structure–activity relationships, biosynthetic studies, first syntheses, and syntheses that lead to the revision of structure or stereochemistry, published up to the year of 2014. More than 190
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benzenediol lactones are described, and over 300 references cited. Keywords: Secondary metabolites; Benzenediol lactones; Dihydroxyphenylacetic acid lactones;
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Resorcylic acid lactones; Bioactivities; Structure-activity relationships.
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Fungi have been proved to be a fertile and important biosource of numerous secondary metabolites with a huge variety of chemical structures and diverse bioactivities. Fungal metabolites are of considerable synthetic interest and remarkable importance as new lead compounds for medicine as well as for plant protection. Importantly, fungal polyketides are one of the largest and most structurally diverse classes of naturally occurring compounds, ranging from simple aromatic metabolites to complex macrocyclic lactones [1-8].
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Among these polyketide secondary metabolites, benzenediol lactone (BDL) is a growing class which is defined by a 1, 3- benzenediol moiety bridged by a macrocyclic lactone ring [9]. They represent a rich scaffold for structural variation, which differ particularly in the degree and positioning of oxidation and unsaturation about the macrolactone ring. Meanwhile, the phenolic hydroxyl groups on the benzene ring can be methylated. The BDL family may be split into resorcylic acid lactones (RALs) and dihydroxyphenylacetic acid lactones (DALs) based on a substituted resorcinol fragment
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fused to α, β-, and β, γ-positions of the macrocyclic lactone ring, respectively (Fig. 1) [10, 11]. To better describe these structures, there exist different numbering systems. Take 14-membered RALs for example, the older system uses the numbers 1-6 for the aromatic ring and 1'-12' for the aliphatic
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macrocycle, whereas the more recent IUPAC system counts the C-atoms from 1-18 (Fig. 2). This situation, although unsatisfactory, did not cause major problems to date, because the number of BDLs was quite limited [12]. Considering the coherence of the previous review, here we retain both systems. Fig. 1. Basic scaffold of benzenediol lactones
Fig. 2. Different numbering systems of 14-membered RALs
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1. Introduction
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To date, over 190 natural BDLs were found in numerous fungi mainly belonging to the genera
Aigialus, Cochliobolus, Curvularia, Fusarium, Humicola, Lasiodiplodia, Penicillium and Pochonia etc. Table 1 shows all the natural BDLs discovered including names, fungal sources and references published between the end of 1953 and July 2014. Although these BDLs are anabolited by many different fungal species, they are known to be produced via a pair of similar collaborating iterative polyketide synthases (iPKSs): a highly reducing iPKS (hrPKS) with product that is further elaborated by a nonreducing iPKS (nrPKS) to yield a 1, 3- benzenediol moiety bridged by a macrolactone [11, 13]. Of course, subtle differences exist between the biosynthetic pathways for different compounds. In recent years, these fungal metabolites were reported to exhibit a wide range of significant 2
ACCEPTED MANUSCRIPT[Benzenediol lactones] biological activities such as inhibition of heat shock protein 90 (Hsp90) and kinases [14], as well as antimicrobial [9], cytotoxic [15], antineoplastic [16], and anti-inflammatory activities [17]. In view of their promising biological activities and interesting structural characteristics, BDLs have increasingly received a great deal of research focus. Since the 1970s, a number of synthetic studies on BDLs have been disclosed. The general synthetic routes usually involve olefin metathesis together with some classical chemical reactions (such as the Heck coupling reaction, the Witting reaction, the Mitsunobu reaction, the Stille coupling reaction, Diels-Alder reaction etc) [18].
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Some BDLs have already been mentioned in a number of certain bioactivity reviews [19-23]. However, these authors cover only a fraction of all known BDLs, since their articles naturally omit the compounds with other activities not included in their reviews. In addition, the resorcylic acid lactones containing a cis-enone or with kinase inhibitory activities of this family have been frequently reviewed by several authors [24-26]. In 2007, Winssinger and Barluenga published a topical review article
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focused on the biosynthesis, chemical synthesis, and biological activity of RALs covered the literature up to 2007. Yet, it only described ten typical RALs in detail [9]. Recently, a review from Xu et al. [18] described 60 resorcinolic macrolides concerning their isolation, bioactivities, biosyntheses, and representative chemical syntheses in recent decades. According to their literature, over 60 different
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resorcinolic macrolides are produced by fungi. However, we found a significantly higher number of relevant fungal metabolites up to 2014: Around 190 compounds are presented in this review. In this review we survey the chemical and biological literatures regarding the isolation, structure elucidation, biological activities, biosyntheses, and chemical syntheses of BDL derivatives from nature. Additionally, those available structure-activity relationships and action mechanisms of some bioactive compounds will also be discussed. We focus on work that has appeared in the literatures up to July 2014. We also hope that we can provide some references for further development and utilization of this
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kind of natural compounds. For ease of illustration and comparison, these natural products are divided into six subclasses according to their ring sizes and structural characteristics: 8-membered BDLs, 10-membered BDLs, 12-membered BDLs, 13-membered BDLs, 14-membered BDLs and other BDLs. Table 1. Benzenediol lactones (BDLs) Name (stereochemistry) (alternative name)
Producing Species
References
Coryoctalactone A (1)
Corynespora cassiicola
[27]
Coryoctalactone B (2)
Corynespora cassiicola
[27]
Coryoctalactone C (3)
Corynespora cassiicola
[27]
Coryoctalactone D (4)
Corynespora cassiicola
[27]
Coryoctalactone E (5)
Corynespora cassiicola
[27]
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Benzenediol octalactone
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Benzenediol decalactone Sporostatin (6)
Sporormiella sp.
[28]
Xestodecalactone A (7)
Penicillium cf. montanense
[31]
Xestodecalactone B (8)
Penicillium cf. montanense
[31]
Xestodecalactone C (9)
Penicillium cf. montanense
[31]
Xestodecalactone D (10)
Corynespora cassiicola
[36]
Xestodecalactone E (11)
Corynespora cassiicola
[36]
Xestodecalactone F (12)
Corynespora cassiicola
[36]
(3R,5R)-Sonnerlactone (13)
Zh6-B1
[37]
3
ACCEPTED MANUSCRIPT[Benzenediol lactones] (3R,5S)-Sonnerlactone (14)
Zh6-B1
[37]
Relgro (15)
Fusarium sp.
[40]
Lasiodiplodia theobromae
[56]
Sarocladium kiliense
[72]
Syncephalastrum racemosum
[70]
unidentified endophytic fungus
[27]
Lasiodiplodia theobromae
[56]
(3R)-Lasiodiplodin (16)
(R)-de-O-Methyllasiodiplodin (17)
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12-Membered benzenediol lactones
Syncephalastrum racemosum
[70]
unidentified endophytic fungus
[27]
5-oxo-Masiodiplodin (18)
Lasiodiplodia theobromae
[58]
(3R, 5R)-Hydroxylasiodiplodin (19)
Lasiodiplodia theobromae
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Syncephalastrum racemosum
[58] [70]
Lasiodiplodia theobromae
[58]
Sarocladium kiliense
[73]
(3R, 4S)-4-Hydroxylasiodiplodin (21)
Lasiodiplodia theobromae
[58]
(3R, 5R)-5-Hydroxyl-de-O-methyllasiodiplodin (22)
Lasiodiplodia theobromae
[58]
unidentified endophytic fungus
[27]
Lasiodiplodia theobromae
[58]
Lasiodiplodia theobromae
[59]
unidentified endophytic fungus
[27]
Syncephalastrum racemosum
[70]
unidentified endophytic fungus
[27]
Lasiodiplodia theobromae
[68]
(3R,4R)-4-Hydroxy-de-O-methyllasiodiplodin (28)
Lasiodiplodia theobromae
[69]
(E)-9-Etheno-de-O-methyllasiodiplodin (29)
Lasiodiplodia theobromae
[69]
(3R, 5S)-5-Hydroxyl-de-O-methyllasiodiplodin (30)
Syncephalastrum racemosum
[70]
(3S, 6R)-6-Hydroxylasiodiplodin (31)
Sarocladium kiliense
[73]
Curvularin (32)
Alternaria cinerariae
[77]
Alternaria zinniae
[78]
Ascochytula obiones
[79]
Beauveria bassiana
[80]
Chrysosporium lobatum
[84]
Cochliobolus spicifer
[81]
Curvularia eragrostidis
[83]
Curvularia inaequalis
[82]
Curvularia lunata
[76]
Curvularia pallescens
[83]
Drechslera australiensis
[85]
Eupenicillium sp.
[86]
Helminthosporium maydis
[87]
Penicillium baradicum
[89]
Penicillium gilmanii
[88]
Penicillium sumatrense
[92]
(3R, 6R)-6-Hydroxyl-de-O-methyllasiodiplodin (23) (3R, 6S)-6-Hydroxylasiodiplodin (24) 6-oxo-de-O-Methyllasiodiplodin (25)
(E)-9-Etheno-lasiodiplodin (26)
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Botryosphaeriodiplodin (27)
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(3R, 5S)-Hydroxylasiodiplodin (20)
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Ulocladium sp.
[94]
α, β-Dehydrocurvularin (33)
Alternaria macrospora
[78]
(also named trans-dehydrocurvularin, dehydrocurvularin)
Alternaria cucumerina
[105]
Alternaria cinerariae
[107]
Alternaria zinniae
[109]
Alternaria tomato
[106]
Aspergillus sp.
[110]
Aspergillus terreus Chrysosporium lobatum Curvularia eragrostidis Curvularia lunata
SC
Curvularia pallescens
RI PT
Penicillium citreo-viride
[111] [84] [83] [76]
[83];
[113]
Drechslera australiensis
[85]
Eupenicillium sp.
[86]
Helminthosporium maydis
[87]
Nectria galligena
[114]
Penicillium turbatum
[90]
Penicillium citreo-viride
[108]
Stemphylium radicinum
[115]
9F series marine fungi
[116]
Ulocladium sp.
[94]
Aspergillus terreus
[114]
Penicillium sp.
[122]
Penicillium citreo-viride
[108]
Penicillium sp.
[112]
Alternaria tomato
[106]
Penicillium citreo-viride
[108]
Penicillium sp.
[112]
Aspergillus terreus
[111]
Penicillium sp.
[122]
Penicillium citreo-viride
[108]
Penicillium sp.
[112]
Curvularia oryzae
[125]
Penicillium citreo-viride
[108]
Penicillium sp.
[112]
Cis-dehydrocurvularin (36)
Penicillium citreo-viride
[91, 108, 121]
12-oxo-Curvularin (37)
Aspergillus sp.
[110]
(also named 7-oxo-curvularin)
Penicillium citreo-viride
[91, 108, 121]
11-β-Hydroxy-12-oxo-curvularin (38)
Aspergillus sp.
[110]
(also named 8-β-Hydroxy-7-oxo-curvularin)
Penicillium citreo-viride
[91, 108, 121]
Penicillium sp.
[112]
Penicillium citreo
[91, 108, 121]
M AN U
Cercospora scirpicola
11-α- Hydroxycurvularin (34a)
EP
11-β- Hydroxycurvularin (34b)
TE D
11-Hydroxycurvularin (34)
AC C
11-Methoxycurvularin (35)
11-α-Methoxycurvularin (35a)
11-β-Methoxycurvularin (35b)
11, 12- Dihydroxycurvularin (39)
5
ACCEPTED MANUSCRIPT[Benzenediol lactones] Penicillium citreo
[91, 108, 121]
Citreofuran (41)
Penicillium citreo-viride
[91, 108, 121]
Penilactone (42)
Penicillium sp.
[126]
10,11-Epoxycurvularin (43)
Penicillium sp.
[126]
β,γ-Dehydrocurvularin (44)
Aspergillus sp.
[110]
E-6-Chloro-10, 11-dehydrocurvularin (45)
Cochliobolus spicifer
[81]
11-O-Acetyldehydrocurvularin (46)
Cercospora scirpicola
[113]
Curvularin-7-O-β-D-glucopyranoside (47)
Beauveria bassiana
[80]
Curvularin-4'-O-methyl-7-O-β-D-glucopyranoside (48)
Beauveria bassiana
6-Hdroxycurvularin-4'-O-methyl-6-O-β-D-glucopyranoside
Beauveria bassiana
(49) Oxacyclododecindione (50)
Exserohilum rostratum
(+)-(15R)-10,11-E-Dehydrocurvularin (51)
Curvularia sp.
(+)-(15R)-12-Hydroxy-10,11-E-dehydrocurvularin (52)
Curvularia sp.
(+)-(15R)-13-Hydroxy-10,11-E-dehydrocurvularin (53)
Curvularia sp.
(+)-(11S,15R)-11-Hydroxycurvularin (54)
Curvularia sp.
(+)-(11R,15R)-11-Hydroxycurvularin (55)
Curvularia sp.
RI PT
12-Hydroxy-10, 11- trans- dehydrocurvularin (40)
[80] [80]
[127]
M AN U
SC
[128] [128] [128] [128] [128]
Curvularia sp.
[128]
Curvularia sp.
[129]
Penicillium sumatrense
[130]
Penicillium sumatrense
[130]
Penicillium sumatrense
[130]
Drechslera phlei
[133]
Penicillium sp.
[131, 135]
Pyrenophora teres
[132]
Drechslera phlei
[133]
Penicillium roseopurpureum
[136]
Penicillium sp.
[131, 135]
Pyrenophora teres
[132]
Drechslera phlei
[133]
Penicillium sp.
[135]
Acremonium zeae
[134]
Drechslera phlei
[133]
Penicillium sp.
[135]
Acremonium zeae
[134]
(R)-7- Methoxydihydroresorcylide (65)
Penicillium sp.
[135]
(S)-7- Methoxydihydroresorcylide (66)
Penicillium sp.
[135]
Dihydroresorcylide (67)
Acremonium zeae
[134]
(68)
Aigialus parvus
[144]
(69)
Aigialus parvus
[144]
Aigialomycin A (70)
Aigialus parvus
[143]
Aigialomycin B (71)
Aigialus parvus
[143]
(+)-(15R)-12-Oxocurvularin (56) Curvulone A (57) Sumalarins A (58) Sumalarins B (59) Sumalarins C (60)
TE D
Trans- resorcylide (61)
EP
Cis-resorcylide (62)
AC C
(R)-7-Hydroxydihydroresorcylide (63)
(S)-7-Hydroxydihydroresorcylide (64)
13-Membered benzenediol lactones
14-Membered benzenediol lactones
6
ACCEPTED MANUSCRIPT[Benzenediol lactones] [157]
Cochliobolus lunatus
[158]
Aigialus parvus
[143]
Paecilomyces sp.
[157]
Aigialus parvus
[143]
Fusarium sp.
[156]
Paecilomyces sp.
[219]
Aigialomycin E (74)
Aigialus parvus
[143]
Aigialomycin F (75)
Aigialus parvus
Aigialomycin C (72)
Aigialomycin D (73)
Paecilomyces sp. Aigialomycin G (76)
Aigialus parvus
1', 2'-Epoxyaigialomycin D (77)
Hypomyces subiculosus
SC
Paecilomyces sp.
RI PT
Paecilomyces sp.
[144] [157] [144] [155] [157]
Cochliobolus lunatus
[158]
Caryospomycins A (79)
Caryospora callicarpa
[159]
Caryospomycins B (80)
Caryospora callicarpa
[159]
Caryospomycins C (81)
Caryospora callicarpa
[159]
Cochliobolus lunatus
[161]
Cochliobolus lunatus
[161]
Cochliobolus lunatus
[161]
Cochliobolus lunatus
[158]
Cochliobolus lunatus
[158]
Cochliobolus lunatus
[158]
Hamigera avellanea
[142]
Hamigera avellanea
[142]
Hamigera avellanea
[165]
Hamigera avellanea
[165]
Hamigera avellanea
[165]
Hamigera avellanea
[165]
Hamigeromycin G (94)
Hamigera avellanea
[165]
Hypothemycin (95)
Aigialus parvus
[143]
Coriolus versicolor
[168]
Hypomyces subiculosis
[155]
Hypomyces trichothecoides
[173, 174]
Phoma sp.
[171]
7', 8'-Dihydrohypothemycin (96)
Hypomyces trichothecoides
[174]
5'-O-Methylhypothemycin (97)
Phoma sp.
[171]
L-783,277 (98)
Phoma sp.
[182]
L-783,290 (99)
Phoma sp.
[182]
4-O-Demethylhypothemycin (100)
Aigialus parvus
[143]
Hypomyces subiculosus
[155]
(101)
Hypomyces subiculosus
[155]
(102)
Hypomyces subiculosus
[155]
Monorden (103)
Chaetomium chiversii
[193]
M AN U
Deoxyaigialomycin C (78)
Cochliomycin A (82) Cochliomycin B (83) Cochliomycin C (84) Cochliomycin D (85) Cochliomycin E (86) Cochliomycin F (87)
Hamigeromycin B (89) Hamigeromycin C (90) Hamigeromycin D (91) Hamigeromycin E (92)
AC C
EP
Hamigeromycin F (93)
TE D
Hamigeromycin A (88)
7
ACCEPTED MANUSCRIPT[Benzenediol lactones] Colletotrichum graminicola
[194]
Humicola fuscoatra,
[200]
Humicola sp.
[195, 196]
Monocillium nordinii
[183, 213]
Neocosmospora sp.
[218]
Neonectria radicicola
[184]
Neophaeosphaeria quadriseptata
[193, 197]
Paecilomyces sp.
[157]
Pochonia chlamydosporia
RI PT
(also named radicicol, or monorden A)
Penicillium luteo-aurantium
[222] [198] [199]
Humicola sp.
Tetrahydromonorden (104)
[196]
SC
(also named monorden B) Humicola sp.
Monorden D (106)
Humicola sp.
(also named pochonin D)
Pochonia chlamdosporia
[212]
Monorden E (107)
Humicola sp.
[196]
M AN U
Monorden C (105)
[196] [196]
Chaetomium chiversii
[193];
Colletotrichum graminicola
[194]
Monocillium nordinii
[213, 214]
Paraphaeosphaeria quadriseptata
[193, 197]
Colletotrichum graminicola
[194]
Monocillium nordinii
[213, 214]
Neocosmospora sp.
[218]
Pochonia chlamydosporia
[212]
Colletotrichum graminicola
[194]
Monocillium nordinii
[213, 214]
Pochonia chlamydosporia
[212]
Monocillium nordinii
[213, 214]
Neocosmospora sp.
[218]
Humicola fuscoatra
[205]
Penicillium sp.
[204]
Monocillium nordinii
[213, 214]
Nordinone (113)
Monocillium nordinii
[214]
Nordinonediol (114)
Monocillium nordinii
[214]
Monocillin II glycoside (115)
Pochonia chlamydosporia
[212]
Monorden analogue-1 (116)
Humicola fuscoatra
[200]
Pochonia chlamdosporia
[216]
Radicicol B (117)
Humicola fuscoatra
[217]
Radicicol C (118)
Humicola fuscoatra
[217]
Radicicol D (119)
Humicola fuscoatra
[217]
Neocosmosin A (120)
Neocosmospora sp.
[218]
Neocosmosin B (121)
Neocosmospora sp.
[218]
Monocillin I (108)
TE D
Monocillin II (109)
Monocillin III (110)
AC C
EP
Monocillin IV (111)
Monocillin V (112)
(also named tetrahydromonocillin I)
8
ACCEPTED MANUSCRIPT[Benzenediol lactones] Neocosmospora sp.
[218]
Paecilomycin A (123)
Paecilomyces sp.
[219]
Paecilomycin B (124)
Paecilomyces sp.
[219]
Paecilomycin C (125)
Paecilomyces sp.
[219]
Paecilomycin D (126)
Paecilomyces sp.
[219]
Paecilomycin E (127)
Paecilomyces sp.
[219]
Paecilomycin F (128)
Cochliobolus lunatus
[158]
Paecilomyces sp.
[219]
RI PT
Neocosmosin C (122)
Paecilomyces sp.
Paecilomycin H (130)
Paecilomyces sp.
Paecilomycin I (131)
Paecilomyces sp.
Paecilomycin J (132)
Paecilomyces sp.
Paecilomycin K (133)
Paecilomyces sp.
Paecilomycin L (134)
Paecilomyces sp.
[221]
Paecilomycin M (135)
Paecilomyces sp.
[221]
Pochonin A (136)
Pochonia chlamydosporia
[212]
Pochonin B (137)
Humicola fuscoatra
[217]
Pochonia chlamydosporia
[212]
Humicola fuscoatra
[217]
Pochonia chlamydosporia
[212]
Pochonia chlamdosporia
[212, 225]
Pochonia chlamdosporia
[212, 225]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Pochonia chlamdosporia
[216]
Fusarium sp.
[156]
Humicola fuscoatra
[217]
Pochonia chlamdosporia
[216]
Pochonin O (149)
Pochonia chlamdosporia
[216]
Pochonin P (150)
Pochonia chlamdosporia
[216]
LL-Z1640-1 (151)
Lederle Culture 21640
[231]
(also named L-783,279)
Cochliobolus lunatus;
[161]
Drechslera portulacae;
[234]
filamentous fungus(MSX63935)
[15]
Paecilomyces sp.
[157]
Sterile fungus (MF6280&6293)
[235]
LL-Z1640-2 (152)
Lederle Culture 21640
[231]
(also named C292, 5Z-7-oxo-zeaenol or L-783,278)
Cochliobolus lunatus
[161, 233]
M AN U
SC
Paecilomycin G (129)
Pochonin C (138)
Pochonin D (106) (also named Monorden D ) Pochonin E (139)
TE D
Pochonin F (140) Pochonin G (141) Pochonin H (142) Pochonin I (143) Pochonin J (144)
Pochonin L (146) Pochonin M (147)
AC C
Pochonin N (148)
EP
Pochonin K (145)
[157] [157] [157] [221] [221]
9
ACCEPTED MANUSCRIPT[Benzenediol lactones] [15, 233]
Sterile fungus (MF6280&6293)
[235]
LL-Z1640-3 (153)
Lederle Culture 21640
[231]
LL-Z1640-4 (154)
Lederle Culture 21640
[231]
Zeaenol (155)
Cochliobolus lunatus
[232]
Drechslera portulacae
[234]
filamentous fungus (MSX63935)
[15]
Paecilomyces sp.
[157]
(5E)-7-oxo-Zeaenol (156)
Cochliobolus lunatus
(also named (7'E)-6'-oxozeaenol)
Drechslera portulacae
RI PT
filamentous fungus (MSX63935)
[158, 233] [234] [15]
5,6-Dihydo-5-methoxy-7-oxo-zeaenol (157)
Cochliobolus lunatus
[233]
15-O-Desmethyl-(5Z)-7-oxozeaenol (158)
filamentous fungus (MSX63935)
Zearalenone (ZEA, ZEN) (159)
Fusarium sp.
SC
filamentous fungus (MSX63935)
[15]
[ 242, 277, 279] [220]
13-Formyl-zearalenone (5-formylzearalenone) (160)
Fusarium graminearum
[277]
5, 6-Dehydro-zearalenone (7'-dehydrozearalenone ) (161)
Fusarium graminearum
[277]
Cochliobolus lunatus
[40]
Paecilomyces sp.
[220]
Fusarium graminearum
[271, 272]
Fusarium graminearum
[277];
Streptomyces rimosus
[286]
Penicillium sp.
[300]
Fusarium graminearum
[277]
5-Hydroxy-zearalenol (6' 8'-Dihydroxyzearalene) (163)
Fusarium graminearum
[275]
10-Hydroxy-zearalenone (3'-Hydroxyzearalenones) (164)
Fusarium graminearum
[276]
Fusarium sp.
[273, 274, 277]
Zearalanone (166)
Fusarium sp.
[277]
α-Zearalanol (also named zeranol) (167a)
Fusarium sp.
[277]
Cis-zearalenone (168)
Fusarium sp.
[277]
Cis-α-zearalenol (169a)
Fusarium sp.
[277]
Cunninghamella bainieri
[286]
Cunninghamella bainieri
[286]
Mucor bainieri;
[291, 292, 287, 290]
M AN U
Paecilomyces sp. SC0924
5-Hydroxy-zearalenone (162)
5-Hydroxy-zearalenone (8'-hydroxyzearalenone, F-5-3) (162a)
TE D
5-Epi-hydroxy-zearalenone (8'-Epi-hydroxy-zearalenon, F-5-4) (162b)
10-α-Hydroxy-zearalenone (164a)
EP
10-β -Hydroxy-zearalenone (164b) Zearalenol (ZOL) (165)
α-Zearalenol (165a)
AC C
β-Zearalenol (165b)
β-Zearalanol (also named taleranol) (167b)
Cis-β-zearalenol (169b) 14, 16-Dimethoxyzearalenone (2,4-dimethoxyzearalenone) (170) 16-Methoxyzearalenone
(2-methoxyzearalenone) (171)
Zearalenone-14-β- D-glucopyranoside (172)
Rhizopus sp.; Thamnidium elegans
10
ACCEPTED MANUSCRIPT[Benzenediol lactones] Fusarium graminearum
[288]
5'-Hydroxyzearalenol (174)
Fusarium sp.
[40, 288]
8'-Hydroxyzearalanone (175)
Penicillium sp.
[300]
2'-Hydroxyzearalanol (176)
Penicillium sp.
[300]
Zearalenone-11, 12-oxide (177)
Fusarium graminearum
[301]
Zearalenone-11, 12-dihydrodiol (178)
Fusarium graminearum
[301]
10-Oxo-zearalenone (10-keto-ZEA) (179)
Fusarium graminearum
[301]
5'-Hydroxyzearalenone (180)
Fusarium sp.
[40]
Trans-7', 8'-dehydrozearalenol (181)
Paecilomyces sp.
Radicicol A (182)
Cochliobolus lunatus
(also named 89-250904-F1)
Hamigera avellanea
Ro 09-2210 (183)
Curvularia sp.
Queenslandon (184)
Chrysosporium queenslandicum
Cryptosporiopsin A (185)
Cryptosporiopsis sp.
[309]
Y5-02-B (186)
Unknown
[310]
Y5-02-C (187)
Unknown
Apralactone A (188)
Curvularia sp.
[128]
Menisporopsis theobromae
[311]
2. Overview of BDLs
[220] [233] [142] [306] [307]
[310]
2.1 8-Membered benzenediol lactones (Benzenediol octalactones)
TE D
Fig. 3. The structures of 8-membered benzenediol lactones (benzenediol octalactones)
To date, coryoctalactones A–E (1-5) (Table 1 and Fig. 3), isolated from Corynespora cassiicola
EP
(JCM 23.3), an endophyte of the mangrove plant Laguncularia racemosa (Combretacaeae) from the island of Hainan, China are the only members of benzenediol octalactones [27]. The relative stereochemistry of coryoctalactones were determined on the basis of one and two-dimensional NMR spectroscopy as well as by high resolution mass spectrometry. The absolute configuration of the side
AC C
5 6 7 8 9 10 11 12 13 14 15 16 17 18
SC
M AN U
Menisporopsin A (189)
1 2 3 4
RI PT
Zearalenone-14-sulfate (ZEN-4-sulfate) (173)
chain hydroxyl C in 1–3 and 5 were tentatively assigned as “R” based on biogenetic consideration in comparison with xestodecalactones D–F. Moreover, the comparison of the optical rotation value of 3 with those of 1 and 2 as well as comparison of NMR data of C-9 and H-9 indicated that 2 and 3 share identical configuration at C-9, and 1 and 2 are epimers at C-9. All isolated compounds were evaluated for their antimicrobial, cytotoxic, and antitrypanosomal activities, but no significant results were obtained. 2.2 10-Membered benzenediol lactones (benzenediol decalactones) Fig. 4. The structures of 10-membered benzenediol lactones (benzenediol decalactones)
11
RI PT
ACCEPTED MANUSCRIPT[Benzenediol lactones]
To data, only ten examples of 10-membered benzenediol lactones have been reported, from marine or terrestrial fungi, namely, sporostatin (6), xestodecalactones A-F (7-12), sonnerlactones (13-14), relgro (15) (Table 1 and Fig. 4). Among them relgro and sonnerlactones belong to
M AN U
10-membered RALs and the other compounds belong to 10-membered DALs.
The first natural 10-membered benzenediol lactone, sporostatin (6), was isolated from the fermentation filtrate of the fungus, Sporormiella sp. M5032 in 1997 by Kinoshita et al [28]. The structure of 6 was secured by an X-ray diffraction study [28], but the absolute configuration was reported by its first total synthesis in 2009 [29]. Sporostatin has been found to have an inhibitory effect on cyclic adenosine 3', 5'-monophosphate phosphodiesterase (cAMP-PDE) with an IC50 value of 41 µg/mL. Further biological evaluation indicated that 6 was a specific kinase inhibitor in vitro whose IC50
TE D
values were 0.1 µg/mL for EGF receptor kinase, 3 µg/mL for ErbB-2, and 100 µg/mL or greater for other kinases, including the platelet derived growth factor (PDGF) receptor, ν-src and protein kinase. Kinetic analyses revealed that inhibition of EGF receptor kinase and cAMP-PDE by sporostatin was noncompetitive either with substrate or with ATP [28, 30]. The xestodecalactones A-C (7-9) were secondary metabolites of a fungus Penicillium cf.
EP
montanense obtained from the marine sponge Xestospongia exigua, and the constitutions, stereostructures including the relative configurations of 8 and 9 were initially established using online HPLC-NMR, ESI-MS/MS, and CD spectra analysis after isolating these compounds [31]. The absolute configurations at C-11 of 7-9 were initially reported as S; however, they were later revised as R until
AC C
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
SC
1
their total syntheses were accomplished and reported during the period 2004 to 2007 [32-34]. Xestodecalactone B produced 25, 12, 7 mm inhibition zones against Candida albicans at 100, 50, 20 µmol, respectively [31]. It was also noted that xestodecalactone A has been patented for antitumor activity [35]. In 2012, the chemical investigation on the ethyl acetate extract of C. cassiicola from leaf tissues of the mangrove plant L. racemosa collected at Hainan Island in China, led to the isolation of xestodecalactones D–F (10-12) [36]. The structures of 10-12 were determined by analysis of NMR and MS data. The relative configuration of xestodecalactone D was obtained from a careful analysis of the coupling constants observed in the well resolved 1D 1H NMR spectrum, as well as from ROESY correlations. Their absolute configurations were assigned by TDDFT ECD calculations of their solution conformers, proving that they belong to the (11S) series of xestodecalactones, opposite to the (11R) configuration of the known xestodecalactones A–C. In this paper, the cytotoxic, antibacterial, antifungal and antitrypanosomal activity of these compounds were investigated, but no positive results 12
ACCEPTED MANUSCRIPT[Benzenediol lactones] were obtained. In 2010, two new metabolites, (3R, 5R)-sonnerlactone (13) and (3R, 5S)-sonnerlactone (14), were isolated from the mangrove endophytic fungus strain Zh6-B1 obtained from the bark of Sonneratia apetala growing in Zhuhai, Guangdong, China [37]. The absolute configuration of 13 was determined by single-crystal X-ray analysis and spectroscopic data. While 14 was deduced by NOESY analysis and comparing circular dichroism spectroscopy with compound 13. Both sonnerlactones (13, 14) exhibited weak anti-proliferative activity against multidrug-resistant human oral floor carcinoma cell lines
RI PT
(KV/MDR) (42.4% and 41.6%, respectively, at 100 µM). The stereoselective synthesis of 13 and 14 has been accomplished starting from L-aspartic acid [38]. The key steps involved asymmetric allylation, Alder–Rickert reaction and Mitsunobu macrolactonization.
Apart from the natural benzenediol decalactones as described above, a novel compound, relgro (15), was mentioned incidentally as an artificial product for the purpose of active test in 1973 [39]. Up
SC
to 2011, it was isolated and elucidated together with other 14-membered RALs from the seagrass-derived fungus Fusarium sp. PSU-ES73 [40]. Antimicrobial activity test showed that it was inactive against S. aureus ATCC25923, methicillin-resistant S. aureus SK1 and Cryptococcus 14-membered RALs together isolated. 2.3 12-Membered benzenediol lactones
M AN U
neoformans ATCC90113. We presumed that the structure may be related to the rearrangement from the
The number of natural 12-membered benzenediol lactones reported by July of 2014 is 53. This group is distributed in more than 30 species and can be divided into three subgroups: lasiodiplodin macrolides (RAL12), curvularin macrolides (DAL12) and other 12-membered benzenediol lactones. Lasiodiplodin macrolides (RAL12)
Fig. 5. The structures of lasiodiplodin macrolides (RAL12)
AC C
EP
TE D
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
24 25 26
To date, 16 lasiodiplodins, 16-31 (Table 1 and Fig. 5), have been produced by fungi Lasiodiplodia theobromae (syns. Botryodiplodia theobromae and Diplodia gossypina, teleomorph Botryosphaeria 13
ACCEPTED MANUSCRIPT[Benzenediol lactones] rodina), Sarocladium kiliense and Syncephalastrum racemosum, as well as various plants, Euphorbia splendens [41], Arnebia euchroma [42], E. fidjian [43], Annona dioica [44], Dioclea violacea [45], Durio zibethinus [46], Pholidota yunnanensis [47], Cibotium barometz [48], Osbeckia opipara [49], Ficus nervosa[50], Cyphostemma greveana [51], Ampelopsis japonica [52], Macroptilium lathyroides [53], and Caesalpinia minax [54]. Among them, L. theobromae, the common pathogenic fungi isolated in the tropics and subtropics on a variety of host plants, was found to be a remarkable producer of lasiodiplodins. Additionally, it should be noted that several authors assumed that lasiodiplodins may
RI PT
not be plant metabolites but may be from fungal epiphytes or endophytes [55].
(3R)-Lasiodiplodin (16) and (R)-de-O-methyllasiodiplodin (17) were the first members of 12-membered resorcylic acid lactone (RAL12) subclass of the benzenediol lactone (BDL) family to be discovered and were isolated from the cultural filtrate of L. theobromae S22L by Aldridge et al. in 1971 [56]. Later, another seven metabolites, 5-oxo-lasiodiplodin (18), (3R, 5R)-hydroxylasiodiplodin (3R,
5S)-hydroxylasiodiplodin
(20),
(3R,
4S)-4-hydroxylasiodiplodin
(21),
(3R,
SC
(19),
5R)-5-hydroxyl-de-O-methyllasiodiplodin (22), (3R, 6R)-6-hydroxyl-de-O-methyllasiodiplodin (23) and (3R, 6S)-6-hydroxylasiodiplodin (24) were also isolated from the fermentation broth and mycelium of L. theobromae IFO 31059 [57-59]. The relative configuration of 16 was assigned by single-crystal
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X-ray, whereas the absolute stereochemistry at C-3, initially deduced to be S from chemical reduction to afford phenyl-2-nonanol, was later revised to R on the basis of the synthetic studies [41, 56, 60-63]. The structures including absolute configurations, of the other compounds from L. theobromae were determined by means of spectroscopic analyses, mainly 1D and 2D NMR, the modified Mosher’s method, and chemical derivation. Especially, the S-configuration of C-3 in compounds 18-20 deduced from the structure of 16 based on the comparisons of spectral data in the previous report [57] also needs to be revised to R. Compounds 18-24 were found be active in potato micro-tuber induction at a
TE D
concentration of 10-3-10-4 M and the activity of 21 was stronger than that of the others [57-59]. We presumed that the hydroxyl was essential for potato micro-tuber inducing activity, and S-configuration has higher activity. The biosynthetic pathways of 16 and 20 in L. theobromae have been studied by Kashima with 13C-labeled acetate tracer experiments [64, 65], and the biosynthetic gene clusters was first identified by Xu et al. [66].
EP
In 2006, two new 12-membered resorcylic acid lactones, namely 6-oxo-de-O-methyllasiodiplodin (25) and E-9-etheno-lasiodiplodin (26), together with 16, 17 and 22, were isolated from the mycelium extracts of an unidentified endophytic fungus (No. ZZF36) obtained from a brown alga (Sargassum sp.) collected from Zhanjiang sea area, China [67]. The structure of 25 was confirmed by X-ray
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
crystallographic analysis. In this paper, (3R)-lasiodiplodin (16), de-O-methyllasiodiplodin (17) showed in vitro antimicrobial active against Staphylococcus aureus, Bacillus subtilis, and F. oxysporum. The bioassay result implied that C-13 and C-15 hydroxyls of lasiodiplodins probably may enhance their antibiotic activities. In 2009, one new lasiodiplodin derivative, named botryosphaeriodiplodin (27) together with 16, 19 and 20, were isolated from an endophytic fungus B. rhodina PSU-M114, which was obtained from the leaves of Garcinia mangostana collected in Suratthani Province, Thailand [68]. The absolute configuration at C-3 in 27 was assumed to analogous to that of 16, while the C-7 stereochemistry was not performed as 27 was obtained in low quantity. In this paper, (3R)-lasiodiplodin (16) exhibited antibacterial activity against S. aureus and methicillin-resistant S. aureus with the respective MIC values of 64 and 128 mg/mL. In 2014, two further lasiodiplodins, (3R, 4R)-4-hydroxy-de-O-methyl-lasiodiplodin (28) and (E)-9-etheno-de-O-methyl-lasiodiplodin (29), together with 17, 23 and 25, from a cytotoxic extract obtained from a culture of L. theobromae, an 14
ACCEPTED MANUSCRIPT[Benzenediol lactones] endophyte from the root tissues of Mapania kurzii (Cyperaceae) from the Malaysian rain forest, were characterized on microgram scale (capillary NMR probe) [69]. The structures including absolute configurations, of the other compounds were determined by means of spectroscopic analyses by analogy with the data for the known lasiodiplodins. The cultural extract was found to biologically active against the P388 murine leukaemia cell line (>80% growth inhibition) [69]. Interestingly, lasiodiplodins isolated from the plant have been previously reported to have antileukemic activities [41].
RI PT
The crude EtOAc extract of the strain S. racemosum from soil in tropical and subtropical regions was found to show cytotoxicity against cholangiocarcinoma cell line KKU-M156 with an IC50 value of 18.02 µg/mL. Bioassay-guided fractionation of this fungal extract led to the isolation of five lasiodiplodins,
(3R,
5S)-5-hydroxy-de-O-methyllasiodiplodin
de-O-methyllasiodiplodin
(17)
(25)
(3R)-lasiodiplodin
5R)-5-hydroxy-de-O-methyllasiodiplodin [70].
Compound
30
showed
(16),
(22)
cytotoxicity
and
against
SC
6-oxo-de-O-methyllasiodiplodin
(3R,
(30),
cholangiocarcinoma, KKU-M139, KKU-M156, and KKU-M213 cell lines with IC50 values in the range of 14.30-19.04 µg/mL, while 17 showed cytotoxicity against KB, BC1, and NCI-H187 cell lines with IC50 values of 12.67, 9.65, and 11.07 µg/mL, respectively. In addition, compound 16 showed
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cytotoxicity against KB, BC1 and NCI-H187 cell lines with IC50 values of 20.77, 25.89, and 20.89 µg/mL, respectively. The first stereo selective total synthesis of 30 and 22 was finished by Yadav et al in 2010 [71]. In
2013,
Yuan
et
al.
reported
the
isolation
and
structure
elucidation
of
(3S,
6R)-6-hydroxylasiodiplodin (31), (3R)-lasiodiplodin (16), and (3R, 5S)-5-hydroxylasiodiplodin (20) from an endophytic fungus S. kiliense grown in rice medium isolated from the gut of healthy Apriona germari (Hope) collected from the campus of Jiangsu Normal University, Jiangsu Province, China [72].
TE D
The structure of 31 was elucidated by a combination of spectroscopic data interpretation, single-crystal X-ray diffraction analysis, and modified Mosher’s method. The absolute configuration at C-6 was determined by a modified Mosher’s method, based on the analysis of differences in proton chemical shifts between the (R), (+) -and (S), (−)-α-methoxy-α-(trifluoromethyl) phenylacetyl (MTPA) esters of 31. The absolute configuration at C-3 was deduced from the relative configuration of C-3 with C-6 by
EP
the X-ray diffraction analysis. The result indicated S configuration for C-3 in lasiodiplodin analogues also exist in nature.
(3R)-Lasiodiplodin (16) and (R)-de-O-methyllasiodiplodin (17) are the most widely studied metabolites in the lasiodiplodin series. (3R)-Lasiodiplodin (16), isolated from plant C. greveana, was
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
found to be active with IC50=0.045 µg/mL against the A2783 ovarian cancer cell line [51]. In 2007, 16 was revealed to be phytotoxic by blocking the electron transport chain in thylakoids at multiple targets that were different from those of current herbicides [73]. De-O-methyllasiodiplodin (17) obtained in the roots of A. euchroma (a traditional Chinese medicine), was found to be responsible, at least in part, for the pharmacological properties of the plant extracts as the result of its efficient inhibition of prostaglandin biosynthesis [55, 63]. In 2010, 17 was reported to be a potent inhibitor of pancreatic lipase (PL) (IC50=4.73 µmol/L), an enzyme that plays a key role in the efficient digestion of triglycerides and that was a target for treating obesity [74]. In 2011, 17 was found to be a novel, natural, non-steroidal mineralocorticoid receptor (MR) antagonist (IC50= 8.93 µmol/L) and an efficient therapeutic target for the treatment of hypertension and other cardiovascular diseases [75]. In this paper, the authors assumed that the acetylation at phenolic hydroxyl groups in analogs of 17 can increase the antagonistic effect against MR and the ring size of the lactone was also very crucial for its activity [75]. 15
ACCEPTED MANUSCRIPT[Benzenediol lactones] It should be noted that this is the first macrolide compound found to behave as MR antagonist to date, different from the other nonsteroidal MR antagonists. Curvularin macrolides (DAL12) Fig. 6. The structures of curvularin macrolides (DAL12)
AC C
EP
TE D
M AN U
SC
RI PT
1 2 3 4
5 6 7
This group including 30 compounds, 32-60 (Table 1 and Fig. 6), is a subclass of DALs with a 12-membered ring system. These compounds almost apparently stem from varied oxidation levels at 16
ACCEPTED MANUSCRIPT[Benzenediol lactones] the C-11 and C-12 position. They are produced by some fungal species mainly from different ascomycete species including Alternaria, Aspergillus, Curvularia, and Penicillium spp. Curvularin (32), the best known member of the curvularin family, was originally isolated as an antifungal agent from the culture filtrate of a species of Curvularia by Musgrave in 1956 [76] and later reisolated from a number of phytopathogenic fungal genera such as Alternaria [77, 78], Ascochytula [79], Beauveria [80], Cochliobolus [81], Curvularia [82, 83], Chrysosporium [84], Drechslera [85], Eupenicillium [86], Helminthosporium [87], Penicillium [88-93], Ulocladium [94] etc and from the
RI PT
root extract of Patrinia scabra plant [95, 96]. The structure of 32 was established by spectroscopic, X-ray and synthetic studies [97-103] and it was usually synthesized based on the Alder–Rickert strategy [100, 102]. Another well known curvularin-type compound, α, β-dehydrocurvularin (trans-dehydrocurvularin) (33), which features a trans double bond in C-10 - C-11 usually co-occurs with curvularin in fungi [78, 83-85, 90, 104-112]. Besides, it was also independently found from Cercospora scirpicola [113], Nectria galligena [114], Stemphylium radicinum [115] and several 9F
SC
series marine fungi [116]. Early biosynthetic studies supported that α, β-dehydrocurvularin was a polyketide product, which was excreted from the cells and reduced to curvularin by extracelullar enzymes [107, 117]. Recently, Molnár’s group predicted the biosynthesis of 33 and revealed
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collaborating hrPKS-nrPKS pairs whose efficient heterologous expression in Saccharomyces cerevisiae provided a convenient access to the DAL12 scaffolds [13].
Both curvularin (32) and α, β-dehydrocurvularin (33), have shown non-specific phytotoxic activity e.g. against Zinnia elegans and Cirsium arvense [106-107, 118], selective antimicrobial activity e.g. against B. subtilis, S. aureus, and Escherichia coli [83, 111], inhibition of TGF-b signaling activities (IC50 = 34.2 and 1.7 µM, respectively) [118], cytotoxic activities against different human tumour cell lines like A549 (IC50 = 13.91±0.15 and 2.10±0.33 µM, respectively), HeLa (IC50 = 25.64
TE D
±0.37 and 21.01±0.19 µM, respectively), MDA-MB-231 (IC50 = 1.3±0.37 and 9.34±0.38 µM, respectively) and MCF-7 (IC50 = 21.89±0.19 and 11.19±0.31 µM, respectively) [84]. Additionally, 32 has been revealed to reduce the expression of the proinflammatory enzyme iNOS in a glucocorticoid-resistant model of rheumatoid arthritis by inhibiting the JAK/Stat signaling pathway [96, 119-120]. It also exhibited 80% acetylcholinesterase (AChE) inhibitory activity [84], and had the
EP
antioxidant activity of H. maydis FBF at a high concentration [87]. While compound 33 showed good superoxide anion scavenging activity with an EC50 value of 16.71 µg/mL [84] and it was also active against COLO 205 with an IC50 of 7.9 µM [84]. Taking together, the IC50 values of 33 were almost always one order of magnitude higher than those of 32 against the corresponding test cell lines except
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
for MDA-MB-231 cell line. However, the presence of a double bond is the only structural difference between two compounds (as one counterpart), which might be one of the important structural property essential for effective interaction in the bioactive profiles. Ten new members of the curvularin family, which include 11-α-hydroxycurvularin (34a),
11-β-hydroxycurvularin (34b), cis-dehydrocurvularin
(36),
11-α-methoxycurvularin 12-oxo-curvularin
(37),
(35a), 11-β-methoxycurvularin
(35b),
11-β-hydroxy-12-oxo-curvularin
(38),
11,12-dihydroxycurvularin (39), 12-hydroxy-10,11- trans- dehydrocurvularin (40) and citreofuran (41) together with two known 32 and 33, were isolated from the mycelium of the hybrid strain ME 005 derived from P. citreoviride 4692 and 6200, upon fermentation on rice [91, 108, 121]. Their structures were established by spectroscopic data. It is worth mentioning that citreofuran (41) is a structurally unique octaketide derivative belonging to the curvularin family containing a furan ring. Furthermore, these authors still pointed that the abosolute configuration of the biologically active compound 17
ACCEPTED MANUSCRIPT[Benzenediol lactones] 1
previously isolated from A. tomato in 1976 was β-hydroxycurvularin (34b) [106]. Later,
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
11-hydroxycurvularin (34) and 11-methoxycurvularin (35) (the mixtures of 11α- and 11β-epimers) were also reported as metabolites of several fungi such as A. cervinus [111] and Penicillium sp. [122] (Trichonaceae) isolated from the rhizosphere of Anicasanthus thurberi and Fallugia paradoxa, respectively. The author assumed 34 and 35 was probably produced by a Michael-type addition of H2O and MeOH to the enone system of 33 during the processing of these microorganisms, respectively [111]. In 2007, the first total synthesis of 35a and 35b was reported by Liang et al., in which the
RI PT
spectral data of originally proposed structure for 11-methoxycurvularin were pointed to 35a [123]. The curvularin derivatives 32-41 were discovered to have considerable cytotoxicities toward a panel of human cancer cell lines (NCI-H460, MCF-7, SF-268, MIA. Pa Ca-2), with IC50 values ranging from 0.90 to 13.30 µM [111, 122]. They acted as inhibitors in blocking the cell division [81] by specifically disordering the microtubule centers [102] and inducing barrel-shaped spindles [90], and inhibited
SC
Hsp90 [16], a promising target for anticancer drug discovery (Janin 2005). The ability likely originated from the conformation of their macrocyclic ring, which mimiced the M-helicity of the colchicin skeleton, a stereochemical feature known to be important for tubulin binding of these agents [81, 101]. Compounds, 34, 37 and 38, had nematicidal activities against P. penetrans of 35%, 80% and 23% at a
M AN U
respective concentration of 300mg/L [110, 124]. Moreover, 11-α-methoxycurvularin (35a) was independently identified from the crude extract of C. oryzae MTCC 2605 by silica gel column chromatography in 2009 [125]. In this paper, it showed strong antibacterial activities against gram-positive bacteria e.g. S. aureus, B. sphericus with a mean MIC value of 100 µg/mL and gram-negative bacteria e.g. Pseudomonas aeruginosa, P. oleovorans with inhibition zones between 12 to 16 mm, as well as moderate antifungal activity. Against Spodoptera litura 4th instar larvae LD50 was determined to be 205.59 µg/mL [125].
TE D
Recently, the chemical investigation of the endophytic fungus Penicillium sp. obtained from stem tissues of Limonium tubiflorum (from L. tubiflorum growing in Egypt) resulted in the isolation of two new curvularins, named penilactone (42) and 10,11-epoxycurvularin (43), along with four known curvularin-type metabolites (33, 35a, 35b, 36) [126]. Penilactone (42) is characterized by a 4-chromanone ring system formed by connecting the oxygenated aromatic carbon C-7 and CH-11. It
EP
was noteworthy that 42 incorporated a 4-chromanone ring system was rather rare among macrolides. The configuration of 42 and 43 at C-15 was assumed by comparison the of measured [α]D values with those of similarly curvularin-type metabolites [126]. In this paper, compounds (35a and 35b) showed
AC C
pronounced antitrypanosomal activities with MIC values of 4.96 and 9.68 µM, respectively. Compounds (35a, 35b, 36) selectively inhibited the growth of human T cell leukemia cells (Jurkat) (IC50 = 3.9, 2.3, and 5.5 µM, respectively), and human histiocytic lymphoma cells (U937) (IC50 = 1.8, 4.6, 2.5, and 7.6 µM, respectively), and reduced TNFα-induced NF-κB activation as expressed by their IC50 values of 4.7, 10.1, 5.6, and 1.6 µM, respectively [126]. We presume that the presence of a free methoxy group at C-11 is essential for antitrypanosomal activity, whereas trans isomer is more active than cis one. Other well known curvularin analogues included β, γ-dehydrocurvularin (44) isolated from the culture filtrate and mycelial mats of Aspergillus sp. [110], E-6-chloro-10, 11-dehydrocurvularin (45) from C. spicifer [81], 11-O-acetyldehydrocurvularin (46) from C. scirpicola [113]. 44 showed nematicidal activities against P. penetrans of 35% and 87% at a respective concentration of 300 and 1000 mg/L [110]. In 2005, three new curvularin-derived products were obtained during the course of biotransformation of curvularin (32) with B. bassiana ATCC 7159. They were identified as 18
ACCEPTED MANUSCRIPT[Benzenediol lactones] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
curvularin-7-O-β-D-glucopyranoside (47),
curvularin-4'-O-methyl-7-O-β-D-glucopyranoside (48),
36 37 38 39 40 41 42 43 44
oxa-Michael addition of the phenolic hydroxyl group to the α, β-unsaturated ketone moiety. The
6-hydroxycurvularin-4'-O-methyl-7-O-β-D-glucopyranoside (49) which resulted from hydroxylation, glucosidation, and methylglucosidation of the substrate, respectively [80]. In 2008, a new curvularin analogue, oxacyclododecindione (50), was isolated from the fermentations of the fungal strain Exserohilum rostratum IBWF99121, as a potent inhibitor of IL-4 signaling by inhibiting the binding of the activated Stat6 transcription factors to the DNA binding site without affecting tyrosine phosphorylation [127]. The structure of 50 was determined by a combination of spectroscopic
RI PT
techniques. Unfortunately, neither the relative nor the absolute configuration could be determined from the existing data. Later, in a screening for fungal compounds with a cell-based reporter assay, 32, 33 and 50 were found to suppresse the TGF-b inducible activation of a Smad 2/3 dependent transcriptional reporter in HepG2 cells in a dose-dependent manner without displaying cytotoxic effects. Among them, 50 was the most highly potent inhibition with IC50 values of 190-217 nM [119]. We assume that free
SC
methyl groups may enhance the activity.
During the chemical investigation of the cytotoxic extract of the marine-derived fungus Curvularia sp. (strain no. 768), isolated from the red alga Acanthophora spicifera, six novel curvularin-type macrolides, (+)- (15R)- 10,11- E-dehydrocurvularin (51), (+)- (15R)- 12-oxocurvularin (+)- (15R)- 12- hydroxy- 10,11- E- dehydrocurvularin (53), (+)- (15R)- 13- hydroxy- 10,11- E-
M AN U
(52),
dehydrocurvularin (54), and C-11 stereocenter epimers of (+)- (15R)- 11- hydroxycurvularin (55 and 56), were obtained together with a 14-membered macrolide. The planar structures of 51-56 were confirmed by interpretation of extensive 1D and 2D NMR experiments (HMBC, HSQC and COSY). Based on their optical rotation and CD spectra, the configuration at C-15 of newly isolated metabolites 51-56 was assigned as R, which was different from the known curvularin-type compounds as described above. The newly identified metabolites 51 and 53-55 were found to exhibit structure-dependent
TE D
cytotoxic properties. Especially, 51 displayed strong cytotoxicity, about 24-fold more cytotoxic potency than its 13-hydroxy derivative 53, against nine tested human cancer cell lines (BXF 1218L (bladder cancer), BXF T24 (bladder cancer), CNXF SF268 (glioblastoma), LXFA 289L (lung adenocarcinoma), MAXF 401NL (mammary cancer), MEXF 462NL (melanoma), MEXF 514L (melanoma), OVXF 899L (ovarian cancer), and PRXF PC3M (prostate cancer)) in a
EP
concentration-dependent manner (IC50 = 1.25 µM), suggesting that the stereochemistry at C-15 chiral center of the curvularin-type macrolides is not crucial for their cytotoxic activity. In contrast, variations of the oxidation levels around the macrocycle seem to influence the cytotoxic activity of the
AC C
(+)-(15R)-curvularin-type metabolites [128]. Curvulone A (57), another novel (15R)-curvularin-type metabolites has been isolated from a Curvularia sp. associated with a marine red alga Gracilaria folifera, with two known 15R series compounds (51 and 54). Structurally, 57 features a unique benzofuranone ring linked to 12-membered macrolactone, which can be formed by an intramolecular relative configurations of two chiral centres were determined as 10S*, 15R* by X-ray diffraction analysis, and the absolute configuration of 57 was accomplished independently by the solid state TD-DFT ECD method and by measuring the anomalous dispersion effect. The metabolites (51, 54 and 57) had pronounced antibacterial activities against the B. megaterium, antifungal activities against Microbotryum violaceum and Septoria tritici, and were antialgal against Chlorella fusca. Particularly, 57 showed the strong activity against the Gram positive bacterium Bacillus strain 6540 inhibiting 92% of the bacterial growth [129]. More recently, in order to find new bioactive secondary metabolites from marine-derived fungi, 19
ACCEPTED MANUSCRIPT[Benzenediol lactones] three rare curvularin derivatives, sumalarins A–C (58-60), along with three known metabolites (32, 33 and 47), were identified in the cytotoxic extract of P. sumatrense MA-92, a fungus obtained from the rhizosphere of the mangrove Lumnitzera racemosa. 58-60 were the first examples of curvularin derivatives possessing sulfur substitution. Their structures were established by a detailed interpretation of NMR and MS data, including determining the crystal X-ray structure of 58. The authors assumed that 60 was likely produced via Michael addition of the cysteine metabolite 3-mercaptolactate to the double bond of dehydrocurvularin and thus was reminiscent of glutathione detoxification of Michael
RI PT
acceptors in mammalian metabolism. Compounds 58 and 59 can be derived from 60 by esterification or esterification and acylation, respectively. The bioassay results showed that the sulfur-containing curvularin derivatives 58-60 exhibited cytotoxic activities against seven tested tumor cell lines (Du145, HeLa, Huh 7, MCF-7, NCI-H460, SGC-7901, and SW1990) with IC50 values ranging from 3.8 to 10 µM, while 32 was inactive. The data implied that the structural feature of sulfur substitution at C-11 or Novel 12-membered resorcylides Fig. 7. The structures of novel 12-membered resorcylides
SC
a double bond at C-10 significantly increased the cytotoxic activities of the curvularin analogues [130].
To date, 7 12-membered benzenediol lactones including trans-resorcylide (61), cis-resorcylide (62), dihydroresorcylide (67), 7-hydorxyresorcylide enantiomers (63 and 64), and their methyl esters (65 and 66) (Table 1 and Fig. 7), have been included in this type. They are produced by fungi Penicillium spp. [131], Pyrenophora teres [132], D. phlei [133] and Acremonium (Sarocladium) zeae
EP
[134]. Structurally, they are related to both curvularinds and lasiodiplodins, but possess a modified carbon skeleton [131]. The skeleton of these compounds contains one more ketone carbonyl than lasiodiplodin’s. Meanwhile, the ketone carbonyl in these compounds is linked to the isolated benzylic CH2 corresponding to C-10 rather than directly to the aromatic ring in curvularins.
AC C
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
TE D
M AN U
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Trans- (61) and cis-resorcylide (62) were first isolated as new plant growth inhibitors from an
unidentified species of Penicillium by Oyama et al. in 1978 [135]. Later, they were reisolated from another fungus Penicillium SC2193 along with 7-hydorxyresorcylide enantiomers (63 and 64), and their methyl esters (65 and 66) [131]. In 1996, 62 has been isolated from P. roseopurpureum [136]. Besides the genus Penicillium, trans- (61) and cis-resorcylide (62) also was found in P. teres, the cause of net-type net blotch of barley [132], and D. phlei, a pathogenic fungus on timothy grass, along with 63 and 64 [133]. The structures of 61-66 were determined using a combination of spectroscopic techniques with emphasis on NMR spectroscopy. The spectral data indicated that 61 and 62 possess a rather unique structural mark: the cis isomer (62) is characterized by a strong H-bond between the phenol hydroxyl and the lactone carbonyl, while trans isomer (61) lacks that feature [135]. The S-configuration at C-3 of resorcylides was originally assigned on the basis of the chemical degradation of cis-resorcylide [135], and this was later confirmed by total synthesis [137]. In 2008, a new 20
ACCEPTED MANUSCRIPT[Benzenediol lactones]
7-hydroresorcylide (64 and 64) [134]. The configuration of a methyl group in 67 had been originally determined to be the S configuration; however, the optical rotation sign of naturally isolated 67 {[α]25.0 D +15.0 (c 0.33, MeOH)} was opposite to that of the synthetic 67 {[α]24.0 –40.0 (c 0.8, MeOH)}, D indicating that the configuration of naturally isolated 67 most likely needs to further revised [138]. Resorcylides were phytotoxic as demonstrated in leaf puncture wound assays and inhibited
RI PT
seedling root elongation [132-135, 139]. 61 caused necrosis on corn and crabgrass (Digitaria sanguinalis) at 0.06 µg per leaf. At 2 µg/leaf, timothy (Phleum pratense), wild poinsettia, and sunflower (Helianthus annuus) were also very sensitive to 61, while 62 was inactive at 1 µg per leaf. Other saturated resorcylide (63-66) fell midway between the two and retained activity at 0.5 µg per leaf. Compound 61 was a plant growth inhibitor and was >10 times more effective than 62 at inhibiting
SC
seedling root elongation [135]. Additionally, trans-resorcylide (61) exhibited cytotoxicity against a panel of tumor cell lines, anti-microbial activity against Pyricularia oryzae, and was an inhibitor of 15-hydroxyprostaglandin dehydrogenase, whereas 62 does not inhibit that enzyme [140]. Cis-R-(−)-resorcylide (62) specifically inhibits blood coagulation factor XIIIa and may be
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advantageous to enhance fibrinolysis and resolve blood clots [136, 141]. Apparently, the configuration of double bond has a strong impact on bioactivities. 2.4 13-Membered benzenediol lactones
Fig. 8. The structures of 13-membered benzenediol lactones
TE D
21 22 23 24 25 26 27 28 29
of 154 isolates), a protective endophytic fungus of maize, along with the two diastereomers of
Natural occurring 13-membered 1, 3-dihydroxybenzene macrolides are very rare. Only two compounds without definite names were reported as the derivatives of 14-Membered RALs so far. The
EP
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
metabolite, dihydroresorcylide (67), was also revealed to have wide spread occurrence in A. zeae (105
authors thinked that these two 13-membered macrolides (68, 69) (Table 1 and Fig. 8) isolated from the marine mangrove fungus Aigialus parvus BCC 5311 were possibly produced from air oxidation of aigialomycin A and hypothemycin, respectively. Possible mechanism for the production of 68 is
AC C
1 2 3 4 5
proposed in Scheme 1. Rearrangement from a 14-membered to 13- membered macrolides could be explained by carbon migration of hemiacetal [142]. Scheme 1. Possible mechanisms for the production of 13-Membered benzenediol lactones
21
2.5 14-Membered benzenediol lactones
14-Membered benzenediol lactones constituted the largest group of BDLs including more than 100 substances, the majority of which belonged to RALs family. These included aigialomycins, caryospomycins,
cochliomycins,
hamigeromycins,
hypothemycins,
monocillins,
monordens,
neocosmosins, paecilomycins, pochonins, zeaenols and zearalenones etc, which were mainly obtained from fungal species of genera Aigialus, Caryospora, Cochliobolus, Hamigera, Hypomyces,
TE D
Monocillium, Humicola, Neocosmospora, Paecilomyces, Pochonia, Drechslera and Fusarium etc. In addition, only three natural 14-membered benzenediol lactones resembled the DALs. Aigialomycins
EP
Fig. 9. The structures of aigialomycins
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1 2 3 4 5 6 7 8 9 10 11 12
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SC
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
22
M AN U
SC
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
1
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Compounds of this type include 9 RALs, 70-78 (Table 1 and Fig. 9). They were mainly reported as the secondary metabolites of the genus Aigialus.
In the course of screening for novel bioactive compounds from microbial sources, five resorcylic macrolides, aigialomycins A-E (70-74), were isolated from the mangrove fungus, A. parvus BCC 5311, along with previously reported hypothemycin (95) (see in Fig. 13) in 2002 [143]. The structures and
EP
absolute configuration of 70-74 were elucidated by chemical conversions, detailed analysis of the NMR spectroscopic and mass data in conjunction with X-ray data obtained on hypothemycin [143]. Several years later, another six new nonaketide metabolites including aigialomycin F and G (75 and 76), which can be looked as distinct aigialomycin derivatives, were isolated from the same marine
AC C
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
mangrove fungus by the same group [144]. The stereochemistry of 75 and 76 was addressed by conversion to acetonide derivatives. The result that the same compound could be prepared by hydrogenation of 75 and reduction of 76 with NaBH4 revealed that 75 and 76 possessed the same relative stereochemistry. On the basis of these experimental data and by biogenetic correlation to 71, the absolute configurations of 75 and 76 were deduced to be 1'R, 2'S, 4'S, 5'S, 6' S, 10'S and 1'R, 2'S, 4'S, 5'S, 10'S, respectively. Compounds (70-75) displayed weak activity against Plasmodium falciparum K1, cytotoxicities against two cancer cells (KB, BC-1) and Vero cells (African green monkey kidney fibroblast), of which aigialomycin D (73) was the most potent (IC50 were 6.6, 3.0, 18 and 1.8 µg/mL, respectively) [143]. Additionally, 73 also exhibited kinase inhibitory activities [145, 146] (IC50: 6 µM for CDK1/5, 21 µM for CDK2, and 14 µM for GSK) although it did’ t belong to those resorcylic macrolides containing a cis-enone moiety, which are well known as one of the more promising groups of natural products that have recently emerged as new lead structures for kinase 23
ACCEPTED MANUSCRIPT[Benzenediol lactones] 1 2 3 4
inhibition. The result suggested that different RAL scaffolds might inhibit different kinases via various
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
The compounds of this class have been found from other fungi. 1', 2'-Epoxyaigialomycin D (77)
resulting in eight total syntheses [145, 147-153]. In addition, 73 has recently been shown to bind to Hsp90, but does not function as an indiscriminate ATP antagonist [154].
was first isolated from H. subiculosus in 2006 with other hypothemycin analogues [155]. The structure was established by analysis of NMR and MS data, and the relative configurations were assigned by
RI PT
NMR analyses (1H, 13C, HSQC, HMBC, and TOCSY) and performing X-ray crystallographic analysis. The analysis revealed that the structure of 77 was very similar to that of 73, which just bore an epoxide functionality between C-1' and C-2' instead of the trans-olefinic bond [155]. Aigialomycin D (73), isolated from the cultures of Fusarium sp. LN-10, an endophytic fungus originated from the leaves of Melia azedarach in 2011, was revealed to have significant toxicity toward brine shrimp larvae (76.7%
SC
at a concentration of 10 µg/mL) [156]. In 2012, compounds 71-73, 75 and 77, obtained from the mycelial solid culture of Paecilomyces sp. SC0924, were found to have weak activities against Peronophythora litchii in an assessment of antifungal activity by the well plate diffusion method [157].
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Recently, deoxy-aigialomycin C (78) was first reported as a natural product isolated from the sea anemone-derived fungus C. lunatus. Its relative and absolute configurations were confirmed using NOE experiments of its acetonide derivative and the CD exciton chirality method with its pdimethylaminobenzoyl derivative. It exhibited potent antifouling activity at nontoxic concentrations with the EC50 value of 22.5 µg/mL [158]. Previously, 78 was obtained as a new aigialomycin analogue along with epi-Aigialomycin D through the syntheses studies of aigialomycin D [154]. Caryospomycins
Fig. 10. The structures of caryospomycins
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22 23
mechanisms. Consequently, 73 has attracted considerable interest from the synthetic community,
24
Three compounds of this type, 79−81 (Table 1 and Fig. 10), possessed a rare structure in which a 1,2-dimethoxy-4-hydroxybenzene ring fused into the 14-membered macrolides. In 2007, our group
AC C
25 26 27 28 29 30 31 32 33 34 35 36 37
reported the isolation of caryospomycins A-C (79-81), as a result of the investigation of the metabolites with activities against plant parasite nematodes from the fresh-water fungus C. callicarpa YMF1.01026, which was initially isolated from a submerged woody substrate collected from a freshwater habitat in Yunnan Province, China. The chemical structures of 79 − 81 were determined through NMR spectroscopic analysis. The spectra data combined with 2D NMR experiments indicated 80 was a deacetonided derivative of 79, and 81 was an analogue of 80 but with a different oxidation state at C-6'. In this report, these compounds were demonstrated to be active in an in vitro microtiter plate assay and exhibited moderate killing activity against the nematode Bursaphelenchus xylophilus with the LC50 values of 103.1, 105.8, and 105.1 ppm, at 36 hr, respectively [159]. Cochliomycins Fig. 11. The structures of cochliomycins 24
M AN U
SC
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
1
The compounds of this class, 82−87 (Table 1 and Fig. 11), were only obtained from fungus C. lunatus.
Cochliomycins A-B (82-83), two with a rare natural acetonide group, and cochliomycin C (84), one with a 5-chloro-substituted lactone, were isolated from the culture broth of C. lunatus, a fungus
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obtained from the gorgonian Dichotella gemmacea collected in the South China Sea [160]. Their structures were elucidated by extensive spectroscopic analysis including 1D NOE and 2D NOESY experiments and chemical conversions. The only difference between cochliomycin A and B was the position of acetonide group. The absolute configurations of 82 and 83 were further confirmed after treatment of zeaenol (155) with 2, 2-dimethoxypropane in the presence of p-toluenesulfonic acid
EP
(PTSA) resulted in a mixture of cochliomycin A and B. However, cochliomycin C initially published structure 84a, was later revised to 84, which was assigned as 4'S, 5'R, 6'S, 10'S, by the same authors [161]. Interestingly, a transetherification reaction that compound 83 in a solution of CDCl3 slowly can be rearranged to give 82 at room temperature indicated cochliomycin A can arise from cochliomycin B
AC C
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
via a transetherification reaction in which the ether migrated from O-4' to O-6' [160]. Recently, the reinvestigation of the secondary metabolites from the sea anemone-derived fungus C. lunatus (collected from Weizhou coral reef in the South China Sea) led to the isolation of three new 14-membered resorcylic acid lactones, cochliomycins D−F (85-87), and eight known analogues. Detailed analysis of the 1D and 2D NMR spectra established the same planar structures for 85-87. Their absolute configurations were established by the CD exciton chirality method and TDDFT ECD calculations. The result indicated that these compounds were diastereomers differing from each other by the absolute configurations of the 4', 5'-diol chiral centers [158]. In antifouling assays, compound 82, 85 and 87 exhibited potent antifouling activities against the larval settlement of the barnacle B. amphitrite at nontoxic concentrations, with EC50 values of 1.2, 17.3 and 6.67 µg/mL, respectively. Structure−activity relationships suggested that the enone and acetonide functionalities and hydroxy configurations may have obvious influence on antifouling activity. Additionally, only 82 was found to 25
ACCEPTED MANUSCRIPT[Benzenediol lactones] have moderate antibacterial activity against S. aureus with an inhibition zone of 11 mm in diameter at a concentration of 50 µg/mL [158]. Very recently, cochliomycin A was firstly synthesized by Nanda’s group from L-(t)-tartaric acid in 6.5% overall yields employing Keck allylation [162] and then was stereoselectively synthesized based on chiron approach by Wang et al. [163]. Cochliomycin B (83) and zeaenol (155) have been synthesized from natural chiral template ι-arabinose in overall yield of 4.8%, by
Takai
olefination,
Suzuki
coupling,
alkoxide-mediated
transesterification,
and
RCM
Hamigeromycins Fig. 12. The structures of hamigeromycins
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macrocyclization as the crucial steps [164].
EP
This group of 7 compounds 88− − 94 (Table 1 and Fig. 12) features a 1, 2- dimethoxy- 4hydroxybenzene ring and a 14-member macrocyclic lactone ring, which includes a 1'-2' trans double bond, a ketone and one or two hydroxys. These compounds were all isolated from Hamigera avellanea.
AC C
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
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1 2 3 4 5 6 7 8 9
Hamigeromycins A (88) and B (89) were first isolated from the soil fungus H. avellanea BCC
17816 together with radicicol (103) [142]. In a subsequent study, the same team got hamigeromycins C–G (90-94) by altering a liquid fermentation medium (PYGM). The structures and the stereochemistry of these compounds were deduced by analyses of the NMR spectroscopic and mass spectrometry data in combination with chemical means. It should be noted that 88, 90, 91 and 92 were stereoisomers differing from each other in the absolute configurations of the 4', 5'-diol moiety; while 93 and 94 were unusual 5'-keto-analogs, and they were 6'-epimers to each other. Besides, 89 were characterized by containing an oxygen bridge [165]. In a cytotoxicity assay, all compounds were inactive against cancer cell lines (KB, MCF-7, and NCI-H187) at a concentration of 50 mg/mL, whilst compounds 88 and 90 showed weak growth inhibition against Vero cells (African green monkey kidney fibroblasts) with IC50 values of 42 and 13 mg/mL, respectively. All compounds were inactive in an antimalarial activity assay against P. falciparum K1 at 10 mg/mL [165]. Recently, several synthestic 26
ACCEPTED MANUSCRIPT[Benzenediol lactones] pathways of 89 were accomplished [166, 167]. Hypothemycins Fig. 13. The structures of hypothemycins
Compounds in this type are some of the highly oxygenated analogues in the group of 14-membered resorcylic acid lactones. There are 8 compounds, 95−102, within this type (Table 1 and Fig. 13), mainly isolated from genus Hypomyces and Phoma.
As the best known compounds in this type, hypothemycin (95) was originally isolated from H. trichothecoides along with 7', 8'-dihydrohypothemycin (96), and later reisolated from the fungal
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fermentations of A. parvus [143], Coriolus Versicolor [168], H. subiculosis [155] and Phoma sp. [169]. The absolute configuration of 95 had been tentatively determined many times by different methods, which included X-ray analysis using anomalous dispersion of oxygen atoms [168], X-ray analysis of an aigialomycin C4-bromobenzoyl derivative chemically correlated to hypothemycin [143], single crystal X-ray analysis in combination with the new solid-state CD/TDDFT methodology [169], and
EP
stereospecific total synthesis of 95 [170-172]. Both 95 and 96 were active against the protozoan, Tetrahymena furgasoni and the plant pathogenic fungi Ustilago maydis and Botrytis allii [173, 174]. In addition, hypothemycin 95 also exhibited strong antimalarial activity in vitro (IC50=2.2µg/mL) [143] and could identify therapeutic targets in Trypanosoma brucei [175]. Additionally, detailed enzymatic
AC C
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
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SC
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1 2 3
and biochemical studies revealed that 95 inhibited a variety of kinases including MEK1/2 (Kd=17 nM and 38 nM), β-type platelet-derived growth factor receptor (PDGFRβ ) (Kd=900 nM), FMS-like tyrosine kinase-3 (FLT-3) (Kd=90 nM), vascular endothelial growth factor receptor 1 (VEGFR1) (Kd=70
nM)
and
(VEGFR2)
(Kd=10
nM)
at
low
nanomolar
levels,
and
including
extracellular-signal-regulated kinase (ERK) (Kd=8.4 mM) at low micromolar levels [143, 168, 176-177]. It also exhibited potent antitumor efficacy [178-180]. In 2013, Xu et al. [181] made an investigation on the antifungal activity of hypothemycin against P. litchii in vitro and in vivo. They found that 95 inhibited spore germination of P. litchii with the inhibition rate of 90% at 0.39 µg/mL, of 100% at 0.78 µg/mL, caused the ultrastructural modifications of P. litchii, especially the plasma membrane, mitochondria, and vacuoles, reduced decay and suppressed peel browning of postharvest litchi fruit inoculated with P. litchii [181]. Several other hypothemycin analogues were found in fungi as well. 5'-O-Methylhypothemycin (97) 27
ACCEPTED MANUSCRIPT[Benzenediol lactones] was isolated from a Phoma sp. with 95. The structure of 97 was elucidated by means of spectroscopic data analysis [169]. In 1999, L-783,277 (98) and its trans-isomer, L-783,290 (99) were both obtained from a Phoma sp. (ATCC 74403) which was isolated from fruitbody of Helvella acetabulum [182]. 98 found by researchers at Merck was reported to be a potent and irreversible inhibitor of MEK1 with an IC50 at 4 nM, weakly inhibit Lck, and has no activity on Raf, PKA, and PKC to a limited degree. Detailed analysis revealed the inhibition was ATP-competitive associated with the formation of a covalent adduct between the enzyme and the inhibitor. The latter compound (99) showed dramatically
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reduced inhibitory effect on MEK compared to 98 (IC50=300 nM). Three hypothemycin analogues (100-102) were isolated from the fungal strains H. subiculosus DSM 11931 and DSM 11932. The structures of these compounds were elucidated by spectroscopic methods, in combined with chemical conversion of the C-4 hydroxyl group of 100 to an O-methyl group and X-ray crystallographic analysis on a single crystal of 101. One of the analogues, 4-O-demethylhypothemycin (100) exhibited potent and selective cytotoxic activities against cell lines (COL829, HT29 and SKOV3 with IC50 values of Monordens and monocillins Fig. 14. The structures of monordens and monocillins
SC
0.038, 0.10 and 1.8 µM, respectively) with a BRAF mutation [155].
AC C
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
17 18
This subgroup of 14-membered benzenediol lactones with 20 members, (103-119) (Table 1 and 28
ACCEPTED MANUSCRIPT[Benzenediol lactones] Fig. 14), were always isolated together from Humicola sp. Among them, monordens are structurally characterized by a chlorine substitution on the aromatic ring. Monocillins were first isolated from M. nordinii except compound monocillin II glycoside (115). The first 14-membered resorcylic lactone, monorden (103), (also known as monorden A or radicicol), was originally isolated as a potent tranquilizer from Monosporium bonorden in a soil sample collected in the Belgian Congo in 1953 [183]. After ten years, the same molecule was independently obtained from the culture filtrate of Neonectria radicicolas (anam. Cylindrocarpon destructans) (syn.
RI PT
C. radicicola) and was named radicicol [184]. With the establishment of its three chiral centers by X-ray crystal structure in 1987, it was figured out that the initial structure proposed for monorden was incorrect, thus leading to the common acceptance of radicicol as the name of this molecule [185, 186]. In 1992, Lett and Lampilas reported the first total synthesis of radicicol, which confirmed its absolute configurations in three stereocenters [187-189]. The biosyntheses of radicicol in Chaetomium chiversii
SC
and Pochonia chlamydosporia have been studied [190-192]. Later, radicicol has been found to widely distribute in diverse fungal species, including C. chiversii [193], Colletotrichum graminicola [194], Humicola sp. FO-4910 & FO-2942 [195, 196], Neophaeosphaeria quadriseptata [193, 197], Paecilomyces sp. SC0924 [157], P. chlamydosporia var. catenulatum (syn. Diheterospora
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chlamydosporias; Verticillium chlamydosporium) [198], P. luteo-aurantium [199] etc. It was also found to have antifungal activities against Neurospora sitophila, Giberella zeae [199] and A. flavus (MIC > 28 mg/mL) [200], antimalarial activity (with in vivo efficacy) [195], the inhibition of various signal transduction products such as p60v-src, p60c-src and p53/56lyn [201-203], inhibition of HIV-1 Tat transactivation (IC50 =0.027 µM) [204], inhibition of human breast cancer [205] and inhibition in vitro of heat shock protein 90 (Hsp90) (IC50=20 nM) [206-208]. Of them, the inhibition of Hsp90 attracted much attention of many researchers. Further study indicated 103 inhibited the ATPase activity
TE D
of Hsp90 via competitive binding to the N-terminal ADP/ATP binding pocket with nanomolar affinity [207]. However, due to the highly sensitive functionalities of 103, including a Michael acceptor and an epoxide, both of which were readily metabolized, it was inctive to Hsp90 in vivo [209, 210]. Monorden B (tetrahydromonorden) (104) was originally reported as a synthetic compound but later was shown to be secondary metabolites of the fungus Humicola sp. FO-2942, which was
EP
originally discovered as a producing fungus of amidepsines, inhibitors of diacylglycerol acyltransferase (DGAT), by UV spectrum-guided purification [196]. Along with 104, monoden and three new analogues, monordens C to E (105-107) were also isolated from the same fungus [196]. Based on spectroscopic evidence mainly by NMR analysis, the structures of compounds (105-107) were
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
elucidated. The result showed that 105 was 5', 6'-dihydromonorden A, that 106 and 104 lacked the epoxide moiety of 105 and 103, instead by transenone [196, 211]. All monordens (103-107) caused the cell cycle arrest at G1 and G2/M phases in Jurkat cells at a higher concentration of 30 µM. But among them, only monordens A and E (113, 117) showed antifungal activities against A. niger with IC50 values of 12 and 70 µM, respectively [196]. Furthermore, monordens D (106) was found to inhibit Herpes Simplex Virus (HSV) and be antiparasitic against parasitic protozoan Eimeria tenella [212]. Monocillins were closely related to monorden in the aspects of biogenetic derivation, structure and bioactivity. Monocillins I~V (108-112) were first isolated as co-metabolites of monorden (103) from the fungus M. nordinii, a destructive mycoparasite of pine stem rusts in North America in 1980. Among them, only monorden (103) and monocillin I (108) were detected to have significant antifungal activities (MICs = 10-25 mg/mL) against P. debaryanum and weak activities against Rhizoctonia solani (MICs = 100-200 mg/mL) [213]. Seven years later, these metabolites were re-isolated with two 29
ACCEPTED MANUSCRIPT[Benzenediol lactones] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
new structurally related compounds, namely nordinone (113) and nordinonediol (114), from the same
43 44
moderate activities in the memory T cell model of HIV-1 latency (EC50 = 9.1 and 24.9 µM,
fungi [214]. The structures of 108-112 were all identified based on 1H and
13
C-NMR techniques and
mass spectra while that of 113 was confirmed by its direct conversion into radicicol [186, 214]. Structurally, monocillins V, III, II and IV (112, 110, 109 and 111) corresponded to 13-unchlorinated monordens B, C, D and E (104-107), respectively. In recent decades, the monocillins were usually encountered from diverse fungal species. Monocillin II and III (109, 110) and a monocillin II glycoside (115) were isolated from P. chlamydosporia var. catenulate [212]. Monocillins I (108) was separately
RI PT
isolated from N. quadriseptata (Basionym: Paraphaeosphaeria quadriseptata) occurring in the rhizosphere of the Christmas cactus Opuntia leptocaulis, and C. chiversii endophytic on Mormon tea Ephedra fasciculate [193, 197]. Monocillin IV (111) was reported from H. fuscoatra [200] and Penicillium sp. [204] together with 103. 111 displayed antimicrobial activity against the A. flavus (MIC = 56 mg/mL) and inhibitory activity on HIV-1 Tat transactivation (IC50 = 5 µM) [204]. Both monocillin
SC
I and II (108, 109) exhibited selective cytotoxicities against the human cancer cell lines MCF-7 and NCI-H460 (IC50=0.98 and 0.62 mM, respectively), SF-268, and MIA Pa Ca-2, MDAMB-231 [197, 205]. In 2009, 108-110 were reported as bioactive secondary metabolites from C. graminicola (Holomorph: Glomerella graminicola), which displayed significant antifungal activities against A.
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flavus and F. verticillioides in conventional paper disc assay [194]. In the same year, 108-111 were found from P. chlamydosporia TF-0480, and the former three (108-110) and 103 showed WNT-5A expression inhibitory activities with the IC50 values of 1.93, 7.36, 17.62 and 0.19, respectively [216]. It was also noteworthy that monocillin I was well-known for its potent inhibitory activity against Hsp90 as radicicol (103) did [193]. Moreover, monocillin I (108) displayed in vitro activity against the stalkand ear-rot pathogen S. maydis [194]. As expected, the biosyntheses of monocillin I (108) and monocillin II (109) have been proven to use a similar pathway although there are structural variations
TE D
that have been attributed to different oxidation and reduction patterns during the hrPKS step and putative post-PKS enzymatic modifications (e.g. epoxidation and halogenation) [13, 191]. Tichkowsky and Lett reported the total synthesis of 108 and 103 via Miyaura-Suzuki couplings in 2002 [215]. A new monorden analog, monorden analogue-1 (116), along with two known monorden (103) and monocillin IV (111), was isolated from H. fuscoatra NRRL 22980. In this paper, the authors only 13
C-NMR, 2D-NMR, and mass
EP
established the planar structure of 116 after analysis of 1H NMR,
spectral data [200]. In 2009, Shinonaga and co-works reported the reisolation of 116 from P. chlamydosporia var. chlamydosporia and its WNT-5A expression inhibitory activities. Here, the
AC C
relative stereochemistry of 116 was elucidated to be 3α-methyl and 5α-hydroxyl based on 1H-1H coupling constants and NOESY data [216]. More recently, three new radicicol analogues, radicicols B-D (117-119), with four known
compounds radicicol and pochonins B, C, and N, were obtained from a marine-derived fungus H. fuscoatra (UCSC strain no. 108111A) via a bioassay-guided isolation process [217]. The extract of this species was shown to reactivate latent HIV-1 expression in an in vitro model of central memory CD4+ T cells. In this report, the structures of 117-119 were determined on the basis of the molecular formulas and NMR properties of the known compounds. The C-2 stereochemistry of 117-119 was all proposed to be analogous to that of radicicol (103). However, the relative configurations of the secondary alcohols of 118 and 119 were not assigned by NOESY correlation spectroscopy, due to the flexible skeleton lacking α, β, γ, δ-unsaturated ketone functionalities. Compounds 103 and 117 exhibited respectively), while 118 and 119 were inactive, indicating that the epoxide functionality is not required 30
ACCEPTED MANUSCRIPT[Benzenediol lactones] Michael acceptor functionality, something the inactive compounds 118 and 119 do not possess. Neocosmosins
RI PT
Fig. 15. The structures of neocosmosins
In 2013, bioassay-guided fractionation of a fungus Neocosmospora sp. (UM-031509) led to the isolation of three new resorcylic acid lactones, named neocosmosins A (120), B (121), and C (122),
SC
(Fig. 15) along with three known RALs (103, 109 and 111). The structures of new compounds were established on the basis of extensive 1D and 2D-NMR spectroscopic analysis, and mass spectrometric (ESIMS) data in conjunction with X-ray data obtained on 111. In the binding assays in vitro, neocosmosins C showed good binding affinity for the human opioid receptors, which selectively
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inhibited 54.9% of the specific binding of [3H]-enkephalin to CHO-K1 cell membranes expressing human δ-opioid receptors at the concentration of 10 µM (IC50 value of 14.82 µM). Meanwhile, known compounds 103 and 109 also showed potent binding affinities at the µ-opioid receptor (63.5% and 84.9%, respectively). The authors declared that this was the first report on resorcylic acid lactone derivatives with strong affinities for human opioid receptors [218]. Paecilomycins
TE D
Fig. 16. The structures of paecilomycins
EP
5 6 7 8 9 10 11 12 13 14 15 16 17 18
for activation of HIV-1. Moreover, it was also noted that the active compounds (103, 117) all contain a
AC C
1 2 3 4
31
EP
This group of 13 RALs, 123-135 (Table 1 and Fig. 16), are marked as the secondary metabolites of Paecilomyces sp. They are usually highly oxygenated analogues possessing epoxy, hydroxyl, and other oxygen-containing groups on the macrolide ring.
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT[Benzenediol lactones]
During the investigation on the secondary metabolites of Paecilomyces sp. SC0924, Xu et al.
reported the isolation and identification of 13 new benzenediol lactones, named paecilomycins A-M (123-135), together with several known RALs (71-73, 77, 109, 159, 161, 181) from the mycelial solid culture of this fungus, successively [219-221]. Their structures (123-135) were elucidated by extensive NMR analysis and chemical correlations in conjunction with X-ray analysis of paecilomycins A and J. Furthermore, the absolute configurations of paecilomycins J-M (132-135) were assigned by Time-Dependent Density-Functional Theory (TDDFT) calculations of their electronic circular dichroism (CD) spectra after their isolation. Paecilomycins E (127) and F (128) were reversedly assigned in the original isolation report then revised [222] while 135, initially assigned structure 135a, was also revised to 135 [220, 223]. Among them, paecilomycin C and D (125 and 126) having a dihydroisobenzofuranone ring and a polyhydroxylated linear C-10 side chain, which were believed to be biogenetically derived from common macrocyclic RALs through intramolecular SN2-type 32
ACCEPTED MANUSCRIPT[Benzenediol lactones] nucleophilic substitution, were unusual for RALs [144]. It was also very rare in natural RALs that 124 contained an oxygen bridge between C-1' and C-5' to form a pyran ring and 132-135 each contained an ether linkage between C-2' and C-5' to form a tetrahydrofuran (THF) ring. In the assay against the P. falciparum, paecilomycin E (127) displayed antiplasmodial activity against P. falciparum line 3D7 with IC50 value of 20.0 nM, while paecilomycin A, B, F (123, 124, 128) showed moderate activities with IC50 values of 0.78, 3.8, 1.1 µM, respectively. Additionally, 127 and 128 showed moderate activities against P. falciparum line Dd2 with IC50 values of 8.8, 1.7 µM, respectively. Paecilomycin M (135)
RI PT
exhibited weak antifungal activity against P. litchii [157, 181, 221]. In 2012, the stereoselective total synthesis of 128 and the asymmetric total synthesis of 127 were achieved by Srihari [224] and Nanda group [162], respectively. More recently, paecilomycin F (128) was identified from a sea anemone-derived fungus C. lunatus [158]. However, no activity was reported in this paper. Pochonins Fig. 17. The structures of pochonins
14 15 16 17 18 19 20 21 22 23 24 25
AC C
EP
TE D
M AN U
SC
1 2 3 4 5 6 7 8 9 10 11 12 13
These RALs include 16 pochonins, 136-150 (Table 1 and Fig. 17) and 106 (Fig. 14) which were
obtained from P. chlamydosporia var. catenulata strains P0297 and TF-0480 by two different research groups. The entire family of pochonins shared a common structural motif of a 14-membered macrocyclic resorcylic acid lactone core, which was analogous to radicicol (103) except for pochonins F and J (140 and 144) chlorinated at C-5 of the aromatic ring [212, 216]. Differed from the other pochonins, 140 and 144 demonstrated more semblances to the aigialomycin and hypothemycin families of natural products, partly, due to the lack of C-13 chlorination [143, 173]. Interestingly, many pochonins were found to inhibit Hsp90, which may be due to the same pharmacophore as radicicol. Pochonins A-F (136-138, 106, 139-140) were isolated from the strain P. chlamydosporia var. catenulata P0297 [212] while pochonins E-P (139-150) were obtained from P. chlamydosporia var. chlamydosporia TF-0480 [216, 225]. Their structures were elucidated by means of a combination of 33
ACCEPTED MANUSCRIPT[Benzenediol lactones] 1D and 2D spectroscopic techniques. The stereochemistry of the C-7' chlorine in pochonin C (138) had not been firmly established until confirmation by total syntheses [170, 226-227]. While the stereochemistry of the C-6' hydroxyl group in pochonin E and F (139, 140) was first assigned as S-stereochemistry by Shinonaga’s group [225], but later revised R by comparison between the reported proton NMR data of the natural products and the synthetic compounds [228]. An efficient synthesis of ent- pochonin J has been achieved by Martinez-Solorio et al., but does not match the spectroscopic data of pochonin J (144) as initially reported. Further attempts at the structural verification of pochonin J are
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ongoing [229]. Interestingly, we find pochonin D has the same chemical structure as monorden D (106). In the HSV1 (Herpes Simplex Virus 1) replication assay, all the pochonins with epoxide moieties or allyl alcohol moieties (e.g., 136, 137, 139, 140) exhibited bioactivities in the low µM range. Pochonin D (106) which contains a double bond instead of the epoxide ring, showed only cytostatic effects. The authors presumed that the chlorine substituent was probably not essential for the antiviral activity
SC
because monocillin (110) without halogenation also showed inhibitory activity against HSV1 in the nM range. The antiparasitic activities of 136-140 and 106 were tested against Neospora caninum and Eimeria tenella. The result indicated that all the test compounds was not susceptible to N. caninum, but the partly hydrogenated pochonins containing an epoxide function showed moderate activities against
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E. tenella. Among these, pochonin A (136) exhibited the best selectivity toward the parasite. In searching for an inhibitor of WNT-5A expression, radicicol (103) showed the strongest WNT-5A inhibitory activity of the tested samples, however, it also showed relatively high cytotoxicity. The inhibitory activities of 141, 145 and 149 were 10-fold weaker than that of 103 while pochonins 142-144, 147-148 and 150 were practically inactive. However, compared with 103, compound 141 and 149 showed no cytotoxicity at concentrations above 100 µM. The data implied that the 4,5-epoxide or 4,5-E-olefin moieties present in 145 and 149, or 139 and 140, respectively, may be necessary for
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radicicol-type compounds designed to inhibit WNT-5A expression, but the chlorine atom at C-13 may decrease the toxicity against dermal papilla cells.
Besides the species P. chlamydosporia, recently, pochonin N (148) was found in the cultures of Fusarium sp. LN-10, an endophytic fungus originated from the leaves of Melia azedarach, and displayed significant growth inhibitory activity against the brine shrimp Artemia salina at a
EP
concentration of 10 µg/mL, with mortality rate of 82.8% [156]. Pochonins B-C and N (137-138, 148) were also identified from the extract of H. fuscoatra (UCSC strain no. 108111A) with 103. Among them, 137 and 138 showed moderate activities in the memory T cell model of HIV-1 latency [217]. Many pochonins have already been determined the inhibitory activities of Hsp90 by severeal
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43
authors because they are structurally related to radicicol [210, 228]. The result found only pochonin A, D, E and F (136, 106, 139, 140) were active to Hsp90. Of pochonins tested, the best strong compound pochonin D had an affinity for Hsp90 (IC50 = 80 nM), which was 4-fold less than radicicol (IC50 = 20 nM). The epoxide derivative, 136 was also found to be a good inhibitor of Hsp90 (IC50 = 90 nM) whereas the 7′, 8′-diol analog was inactive [19]. The data suggested that neither an epoxide ring nor the dienone was critical for Hsp90 binding. The study on action mechanism indicated these compounds had very different conformations in solution which could rationalize their different biological activities. Interestingly, Moulin E. and his team have exemplified how macrocycle functionalization could not only direct kinase selectivity, but also selectivity between target classes [145, 230]. Zeaenols Fig. 18. The structures of zeaenols
34
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Natural resorcylic lactones of fungal origin from the zeaneols group, 151-158, (Table 1 and Fig. 18) are mainly spread in D. portulacae, C. lunatus, and other unidentified fungus. They exhibit a wide range of biological properties which include oestrogenic, antifungal, phytotoxic and anti-inflammatory activity.
LL-Z1640-1 to 4 (151-154) were first isolated from an unidentified fungus (Lederle Culture 21640) in 1978 [231]. In this paper, the authors found these compounds no particularly interesting activities. They emphasized that these compounds were devoid of anabolic and estrogen-like activity even if they
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were structurally related to zearalenone, a well-known oestrogen hormones. Here, the information about the double bond in 154 was not given. In the same year, Japanese scientists Yuki et al. reported the isolation and structure elucidation of a new metabolite zeaenol (155) from C. lunata grown on potato and (or) Czapek-Dox medium during the chemical studies on aversion-antagonism [232]. In this paper zeaenol was not only confirmed to have the same planar structure to 154 but also the authors
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further revealed that the stereochemistry of the double bond at C-7'-C-8' was trans-configuration while the C-6 hydroxyl had α-configuration orientation. Later, some researchers held the opinion that 154 and 155 were the same compound [233]. In 1992, a paper published the fact that LL-Z1640-1 (151) and zeanol (the same structure as that of 155) cooccured in Drechslera, inhibited plant growth [234].
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
Additionally, we found that compounds L-783,278 and L-783,279 reported from strains (MF6280, MF6293) during the course of screening for potent inhibitors of MEK kinase were 152 and 151, respectively, by comparing their physical and spectroscopic data [235]. Recently, total syntheses of 155 were accomplished by Jana and Nanda [162], Gao et al. [164] and Dakas et al. [236], respectively. In 1999, the capacity of several zearalenone derivatives (152, 155, 156 and 157) to inhibit
lipopolysaccharide
(LPS)-induced
cytokine
production
in
phorbol
12-myristate-13-acetate
(PMA)-treated cultured myelomonocytic cells (U937) was revealed. They exhibited IC50 values of 6 nM, 10 mM, 500 nM and 5 µM, respectively [233]. They were obtained from a 50 L fermentation of Xenova fungus 20416, C. lunatu and named 5Z-7-oxo-zeaenol (152), zeaenol (155), 7-oxo-zeaenol (156) as well as 5, 6-dihydo-5-methoxy-7-oxo-zeaenol (157), respectively. The first total synthesis of 152 was published by Tatsuta et al. [170] in 2001 followed by the Lett et al. [171, 172]. Structurally, we found that 5Z-7-oxo-zeaenol had the same structure as 152. Later, 152 was found to be an 35
ACCEPTED MANUSCRIPT[Benzenediol lactones] ATP-competitive potent and selective inhibitors of TAK1 (IC50=8.1 nmol/L) and ERK2 (IC50=8.0 nmol/L) [17, 237]. Since then, interest in these molecules was renewed. Many 152 analogs were surveyed their inhibitory activities against a variety of kinases and their SARs were presented [25]. With regard to the macrocyclic ring of these molecules, the cis-enone was essential for the activities and modification on the enone moiety or adjacent position (C4) may improve metabolic stability by summarizing the SAR of RALs’ inhibitory activity on kinases established so far. It was also noted that the diol moiety at C8-C9 contributed to the bioactivity, although the C9-OH was more important than
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the C8-OH. Moreover, in the case of the resorcylic ring: addition of N or O-functional group at C13 or C13-C14 fused bicyclic heterocycle can enhance both potency and PK properties [25].
Two new compounds, 15-O-desmethyl-(5Z)-7-oxozeaenol (158) and 7-epi-zeaenol, along with four known RALs (151, 152, 155, 156) were found in filamentous fungal extract of the Mycosynthetix library (MSX 63935; related to Phoma sp.) [15]. Noticeably, the author described 7-epi-zeaenol not a
SC
natural product which was produced by reduction of (5E)-7-oxozeaenol (156) with sodium borohydride. In a series of assays, 152 was the most potent representative of this class of compounds in both cytotoxicity assays against cancer cell lines (MCF-7, H460, SF268, HT-29, MDA-MB-435) and the NF-κB assay [15].
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In the recent studies, LL-Z1640-1 (151), LL-Z1640-2 (152), zeaenol (155), (5E)-7-oxo-Zeaenol (156), have also been found in the culture broth of C. lunatus (obtained from the gorgonian D. gemmacea) [158]. All the four compounds showed potent antifouling activity against the larval settlement of barnacle B. amphitrite (EC50 values of 5.3, 1.82, 1.2, 18.1 µg/mL, respectively). 151 showed moderate cytotoxicities against A549 and HepG2 tumor cell lines with IC50 values of 44.5 and 98.6 µM, respectively, while LL-Z1640-2 showed cytotoxicity against HCT-116 with an IC50 value of 3.24 µM. Among these compounds, only 152 exhibited promising antifungal activity against Pestalotia
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calabae (MIC = 0.39 µM) and excellent agricultural fungicidal activities against Plasmopara viticola and P. infestans on the whole-plant assay [158, 160, 161]. Additionally, it was also noted that 151 found in Paecilomyces sp. showed weak activity against P. litchii [157]. Zearalenone and its structurally related conpounds
EP
Fig. 19. The structures of zearalenone and its structurally related conpounds
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
36
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The compounds (159-181) (Table 1 and Fig. 19) of this group were usually reported as the metabolites of zearalenone in fungi, plants and mammalian systems, as well as the pharmacokinetics. These compounds shared the same carbon backbone close spatial similarity to 17-estradiol [238]. A few review papers have been given on the occurrence, structures and pharmacokinetics of a part of this
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
group [239-241] before. Here we summarize and update the information to date. Compound 159 described as 6-(10-hydroxy-6-oxotrans-1-undecenyl)-ß- resorcyclic acid lactone,
was first isolated from the mycelium of the fungus Gibberella zeae (Syn. F. graminearum) growing as a mould on corn by Stob et al. in 1962 [242], and its chemical structure disclosed by Urry et al, who also coined the name zearalenone (ZEA, ZEN, 159), by combining elements of its predominant occurrence (‘zea’ for maize) with characteristic structural features (‘RAL’ for the resorcylic acid lactone structure, ‘en’ for the olefinic double bond, and ‘one’ for the keto group) [243]. Zearalenone has attracted much attention since it was found. So far, it has been shown to have estrogenicity [244], teratogenicity [245], mutagenicity [246], genotoxicity [247-249], cytotoxicity [248], immunotoxicity [250-253] and hepatonephrotoxicity [254, 255], and to be an enhancer of lipid peroxidation [256] and a cattle-growth stimulant [257, 258] etc. Additionally, it was noted that zearalenone is also one of the most worldwide distributed mycotoxins [259]. The major mycotoxicity of 159 was attributed to its 37
ACCEPTED MANUSCRIPT[Benzenediol lactones] estrogenic effects on genital organs [260] and on reproductive performance [261, 262]. The toxicity to the reproductive system resulted in uterine enlargement, alterations to the reproductive tract, reduced litter size, increased embryolethal resorption, decreased fertility and changes in progesterone and estradiol serum levels in animals [263-267]. Zearalenone (159) is the only member of this family of which the biosynthesis has been genetically characterized, with two reports detailing the identification of the biosynthetic gene cluster from G. zeae [268, 269]. For zearalenone, more than ten synthetic strategies have been designed after its first total synthesis was published in 1967 [270].
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Following the isolation of zearalenone, Bolliger and Tamm reported the identification of four zearalenone-related fungal metabolites in F. graminearum cultures, i.e. 13-formyl-zearalenone (160), 5, 6-dehydro-zearalenone (161), and the two stereoisomers of 5-hydroxy-zearalenone (162a, 162b) in 1972 [271]. The formation of 5-hydroxy-zearalenone (162) was later confirmed by several groups [272-274], and further metabolites were disclosed, i.e. 5-hydroxy-zearalenol (163) [275], the epimers
SC
of 10-hydroxy-zearalenone (164a, 164b) [276].
In 1985, several closely related compounds were detected in fungal incubations, i.e. zearalenone (159), α-zearalenol (165a), β-zearalenol (165b), zearalanone (166), α-zearalanol (also named zeranol) (167a), ß-zearalanol (also named taleranol) (167b), cis-zearalenone (168), as well as the epimers of
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cis-zearalanol (169a, 169b) [277]. Early studies on the metabolism of zearalenone have also disclosed the formation of reductive metabolites, in particular stereoisomers of zearalenol (165a, 165b) [249, 278-281]. Among them, α-Zearalenol (167a) exhibited an even higher estrogenic activity than β-zearalanol (taleranol) (167b) and zearalenone (159) suggesting that the orientation of the hydroxyl group at the aliphatic ring may have a pronounced effect on the oestrogenic activity [274, 282].
α-Zearalanol (167a), also named zeranol, was used as a growth promoter in livestock under the product name Ralgro® [283] because of its high oestrogenic activity. In 2003, a study has demonstrated that the
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catechol metabolites of the 167a had a DNA-damaging potential [247]. Recent investigation indicated that 159, 167a and 167b can interfere with various enzymes involved in steroid metabolism [284, 285]. A series of important papers on zearalenone (159) transformation by fungi and actinomycetes have been published [286, 291, 292,]. Two new transformation products, 2, 4-dimethoxyzearalenone (168) and 2-methoxyzearalenone (171), were obtained from 159 by the cultures of the fungus
EP
Cunninghamella bainieri. They were found not bind to rat oestrogen receptor, indicating a loss of oestrogenicity [286]. A considerable amount of 159 was found to be present as zearalenone14-β-D-glucopyranoside (172) [287] or zearalenone -14- O-sulfate (173) in Fusarium cultures [288, 289]. In 1988, Engelhardt et al. found that 159 can be transformed to 172 by maize cell suspension
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
cultures [287]. 172 can also be produced from 159 by several fungi and actinomycetes such as Rhizopus sp. [291], Mucor bainieri, and Thamnidium elegans etc. [292]. Taking together, there were two sites for glycosylation present in 159, but conjugation in position 14 was strongly favored compared to position 16 [293]. Zearalenone-14-sulfate (formerly known as zearalenone-4-sulfate) (173) was first isolated by
Plasencia and Mirocha from rice inoculated with F. graminearum [288]. El-Sharkawy et al. reported the conversion of zearalenone into 173 by many microorganisms [294] and Berthiller et al. identified zearalenone-14-sulfate as phase II metabolite of zearalenone in the model plant Arabidopsis thaliana [295]. The conjugate most likely retained biological properties of the mycotoxin, since the sulfate moiety was easily cleaved under acidic conditions and in rats [294]. Therefore, 173 was included in analytical methods for the determination of free and masked mycotoxins during the last years [296-298]. 38
ACCEPTED MANUSCRIPT[Benzenediol lactones] Recent decades, some new natural zearalenone derivatives were identificated. In 2008, 5'-hydroxyzearalenol (174) was isolated from the culture broth of a marine-derived fungus Fusarium sp. 05ABR26 with three known compounds (159, 162a and 165). The structure and relative stereochemistry of 174 were elucidated on the basis of spectroscopic data and single-crystal X-ray diffraction data. Of the antifungal and antimitotic activities tested, compound 159 displayed potent inhibitory activity against P. oryzae with a MIC value of 6.25 mg/mL, while compound 162a was much less active; however, 174 and 165 showed no obvious activity [299]. In the same year, two new
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derivatives, 8'-hydroxyzearalanone (175) and 2'-hydroxyzearalanol (176), were isolated from the marine-derived fungus Penicillium sp. along with four known zearalanone derivatives. The structures were elucidated by spectroscopic methods [300]. In 2010, a culture of F. graminearum has been reinvestigated using LC-DAD-MS and, in part, NMR spectroscopy. In addition to confirming most of the previously reported zearalenone metabolites (162a, 162b, 164a, 164b), several novel compounds
SC
were identified. Three of the metabolites were shown to have the structures of zearalenone -11, 12-oxide (177), zearalenone-11, 12-dihydrodiol (178) and 10-keto-zearalenone (179) [301]. As a novel compound, 5'-hydroxyzearalenone (180) and six known ß-resorcylic macrolides (15, 159, 161, 162, 165b and 174) were isolated from the seagrass-derived fungus Fusarium sp. PSU-ES73 in 2011. Their
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structures were established by analysis of spectral data. Among them only the known compound zearalenone (159) displayed weak antibacterial against S. aureus (MIC = 400 µM) and antifungal activities against C. neoformans (MIC = 50.26 µM) [40]. In 2010, trans-7', 8'-dehydrozearalenol (181), along with zearalenones (159 161), were isolated from the mycelial solid culture of Paecilomyces sp. SC0924. Their structures were established by spectroscopic methods and chemical means [220]. Structure-activity relationships for human estrogenic activity in zearalenone mycotoxins have been reported. The 6' functional group had the largest effect on estrogenicity. In both the zearalenone
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series (trans double bond at 1', 2') and the zearalanone series (saturated double bond at 1' , 2') the order of estrogenicity for 6' substituents was α-OH
NH2≥ =O ≈ β-OH
β-OAc. Meanwhile, increased
flexibility in the macrocyclic lactone ring would be expected to favor tighter binding of a zearalenone analog to the estrogen receptor. Because saturation of the 1', 2' double bond increased flexibility of the macrolide ring, the order of estrogenicity for 1', 2' double bond was dihydro
trans
cis. This
EP
order of activity was observed for 6'-ketone derivatives, however, not observed in the present study for derivatives with other 6'-functional groups (α-OH, β-OH, β-OAc), in which case saturating the 1', 2' trans double bond resulted in a 5- to 8-fold reduction in estrogenicity. In addition, resorcinol OH groups contributed little to the binding of zearalenones to the human estrogen receptor. Placing a
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
hydroxyl group near the macrolide ring methyl group enhanced receptor binding, even though the hydroxyl was one carbon further away than in 17β-estradiol [238]. Other 14-membered resorcinylic acid lactones Fig. 20. The structures of other 14-membered resorcinylic acid lactones
39
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ACCEPTED MANUSCRIPT[Benzenediol lactones]
1
Apart from the types as described above, there are some special 14-membered RALs, 182-185,
SC
(Table 1 and Fig. 20).
Radicicol A (87-250904-F1) (182) belongs to the subset of RALs bearing a cis-enone. 182 was first reported as a kinase inhibitor by researchers from Sandoz who identified this fungal metabolite during a screen for IL1ß inhibition [302]. The authors found that 182 accelerated the specific mRNA
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sequences including IL1ß’ s and inhibited tyrosine [233, 302-304]. As a natural product, radicicol A was also isolated from C. lunatus [233] and H. avellanea [142]. In 2005, Marzinzik and co-workers accomplished the first synthesis of 182 [305]. Later, concise syntheses and total syntheses of 182 were also reported by Dakas et al. [304] and Hofmann et al. [24], respectively. In 1998, using high throughput screening of microbial broths (Curvularia sp.), Williams et al identified Ro 09-2210 (183) as a selective inhibitor of MAP kinase kinase 1 (MEK1) with an IC50 at 59 nM. Interestingly, Ro 09-2210 was a highly selective MEK1 inhibitor although it only showed marginal inhibition on other
TE D
kinases such as PKC, PhK, PKA, ZAP-70, and Lck [306].
Queenslandon (184) characterized by a dihydroxyacetone subunit and a highly oxidized benzoic acid, was isolated from the strain C. queenslandicum IFM51121, which was isolated from a soil sample collected in Egypt, and deposited in the collection of Research Center for Pathogenic Fungi and Microbial Toxicoses, Chiba University, Japan. The structure, initially elucidated 184a on the basis of
EP
optical spectroscopy(IR), electrospray (ESI-MS) and high-resolution electron impact mass spectrometry (HREI-MS), one and two dimensional NMR spectroscopy (1H, 13C, DEPT, COSY, HMQC, HMBC, NOESY and TOCSY) [307], was later revised to 184 on the basis of the synthetic studies [308]. It showed distinct activity against fungi including A. nidulans IFM 5369, A. alternata
AC C
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
IFM 41348, P. variotii IFM 40913, P. chrysogenum IFM 40614, A. flavus IFM 41934, A. fumigatus IFM 41088, A. terreus IFM 40851, and A. niger IFM 5368, but not against bacteria such as Micrococcus luteus IFM2066 and B. subtilis PCI 219 [308]. In 2012, in the course of screening for environmentally benign secondary metabolites regulating
the motility and viability of zoospores of P. viticola, cryptosporiopsin A (185) together with hydroxypropan-2', 3'-diol orsellinate, pentapeptide were isolated from the culture of Cryptosporiopsis sp., an endophytic fungus from leaves and branches of Zanthoxylum leprieurii (Rutaceae) [309]. The structures of 185 were elucidated on the basis of spectroscopic analysis and comparison of its spectrometric data with that of ponchonin D. It was noteworthy that resorcylic acid monomethyl ethers with a non-chelated OH group as in 185 were very rare. Cryptosporiopsin A exhibited motility inhibitory and lytic activities against zoospores of the grapevine downy mildew pathogen P. viticola (10µg/mL), inhibitory activity against mycelial growth of two other peronosporomycete 40
ACCEPTED MANUSCRIPT[Benzenediol lactones] Rhizoctonia solani, and displayed cytotoxic activity to brine shrimp larvae [309]. 14-membered dihydroxyphenylacetic acid lactones
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Fig. 21. The structures of 14-membered dihydroxyphenylacetic acid lactones
So far only three compounds, 186-188 (Table 1 and Fig. 21), belong to 14-membered DALs. Two naturally derived 14-membered macrolactones, y5-02-B and y5-02-C (186, 187), have appeared in
SC
a Japanese patent as lead structure concerning the inhibition of neuropeptide Y receptor for anti-obesity programs [310], however the more detailed information could not be obtained. In 2008, the chemical investigation of the cytotoxic extract of the marine-derived fungus Curvularia sp. (strain no. 768), isolated from the red alga A. spicifera, yielded the novel macrolide apralactone A (188). The structure was elucidated by interpretation of its spectroscopic data (1D and 2D NMR, CD, MS, UV and IR). The compound was evaluated for the cytotoxic activity towards a panel of up to 36 human tumor cells and showed concentration-dependent cytotoxicities with a mean IC50 value of 9.87 µM [128]. 2.5 Novel benzenediol lactones
Fig. 22. The structures of novel benzenediol lactones
17 18 19 20 21 22 23 24 25 26 27 28
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5 6 7 8 9 10 11 12 13 14 15 16
phytopathogens, Pythium ultimum, Aphanomyces cochlioides and a basidiomycetous fungus
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1 2 3 4
Menisporopsin A (189) (Table 1 and Fig. 22), a novel BDL, was isolated from a cell extract of
the seed fungus Menisporopsis theobromae. The structure of 189 was elucidated on the basis of spectroscopic analysis and chemical transformations, with the absolute configuration established by application of the modified Mosher’s method and by using chiral HPLC. Menisporopsin A possessed an unprecedented residue, 2, 4-dihydroxy-6-(2, 4-dihydroxy-n-pentyl) benzoic acid. This compound exhibited antimalarial activity with an IC50 value of 4.0 µg/mL, and antimycobacterial activity with a MIC value of 50 µg/mL [311]. 3. Conclusions The review summarized in the above sections illustrates the isolation, structural determination, biogenetic studies, biological evaluation, and synthesis of eight-, ten-, twelve-, thirteen-, fourteen-membered BDL compounds. These natural products have attracted much attention from 41
ACCEPTED MANUSCRIPT[Benzenediol lactones] biologists and chemists because they were isolated from a variety of fungi and possessed fascinating molecular architectures and attractive biological activities. To date, about 190 BDLs with broad-spectrum bioactivities have been identified from the fungi. The members of BDL family are still expanding and the wide-range bioactivities of BDLs are still explored extensively. For this kind of compounds, general biosynthetic pathways have been defined; however, significant pathway branching for individals is still needed to explore. From a chemical synthesis perspective, while several elegant approaches to important BDLs have been reported, synthesizing such compounds through concise and
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modular routes which can be used to extend the diversity of this family remains challenging. From a therapeutic perspective, these fungal lactones may serve as promising lead structures for the development of new therapeutics for the treatment of cancer progression and metastasis as well as chronic fibrotic diseases. However, the preclinical development of some promising results from in vitro studies was hindered due to poor stability in blood plasma and liver microsomes, which need an
SC
extensive medicinal chemistry effort to improve its pharmacokinetic properties. Meanwhile, demand for BDLs in medicinal lead identification and in understanding mechanism of activities will lead to continuing the research in this field. Abbreviations Benzenediol lactones
RALs
Resorcylic acid lactones
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BDLs:
Dihydroxyphenylacetic acid lactones
IUPAC
International union of pure and applied chemistry
iPKSs
Iterative polyketide synthases
nrPKS
Nonreducing iterative polyketide synthases
Hsp90
Heat shock protein 90
NMR
Nuclear magnetic resonace
cAMP-PDE EGF PDGFR ATP HPLC ESIMS CD
Cyclic adenosine 3', 5'-monophosphate phosphodiesterase
50% inhibitory concentration
Extracellular-signal-regulated kinase Beta-type platelet-derived growth factor receptor
Adenosine Triphosphate
EP
IC50
TE D
DALs
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
High performance liquid chromatography
Electrospray ionization mass spectrometry
Circular dichroism
TDDFT
Time-dependent density functional theory
NOESY
Nuclear overhauser effect spectroscopy
MDR
Multidrug-resistant
NCI
Nonsmall cell lung
MTPA
(−)-α-methoxy-α-(trifluoromethyl) phenylacetyl
PL
Pancreatic lipase
MR
Mineralocorticoid receptor
TGF-b
Transforming growth factor-β
A549
Human lung adenocarcinoma epithelial cell line
HeLa
Human Henrietta Lacks cervical cancer cell line
Ehrlich
Mice Ehrlich ascites carcinoma cell line;
MCF-7
Human breast adenocarcinoma cell line 42
ACCEPTED MANUSCRIPT[Benzenediol lactones] Inducible nitric-oxide synthase
AChE
Acetylcholinesterase
FBF
fermented B. formosana
ED50
50% effective dose, ED50
DNA
Deoxyribonucleic acid
COSY
Correlation spectroscopy
HMBC
Heteronuclear multiple bond coherence
HMQC
Heteronuclear multiple quantum correlation Human prostate cancer
Huh
Human hepatocarcinoma
SGC
Human gastric carcinoma
SW1990
Human pancreatic cancer
PYGM
A Liquid Fermentation Medium
PDGFRβ
β-type platelet-derived growth factor receptor
MEK
Methyl ethyl ketone
FLT-3
FMS-like tyrosine kinase-3
VEGFR
Vascular endothelial growth factor receptor
ERK
Extracellular-signal-regulated kinase
PKA
Proteinkinase A
PKC
Proteinkinase C
MIC
Minimum inhibitory concentration
HIV
Human immunodeficiency virus
DGAT
Diacylglycerol acyltransferase
UV
Ultraviolet spectroscopy
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TE D
Herpes simplex virus
THF
tetrahydrofuran
SAR
Structure activity relationship
TNF-α
Tumour necrosis factor-alpha
ZAL
AC C
IL
Zearalenone
EP
ZEA ZEN
RNA
10 11
SC
Du1
HSV
1 2 3 4 5 6 7 8 9
RI PT
iNOS
Zearalenone Zearalanol
Interleukin Ribonucleic Acid
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China
(20762015, 31270091) and the Scientific Research Foundation of Southwest University to Dr. Jinyan Dong (swu109046). References
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Highlights The numerous biological activities of benzenediol lactones have been discussed. The chemical scaffolds of benzenediol lactones have been discussed. The natural sources of benzenediol lactones have been discussed. The structure activity relationships (SAR) of benzenediol lactones for different activities have been discussed in this review.