Anticancer carbazole alkaloids and coumarins from Clausena plants: A review

Chinese Journal of Natural Medicines 2017, 15(12): 08810888

Chinese Journal of Natural Medicines

•Review•

Anticancer carbazole alkaloids and coumarins from Clausena plants: A review HUANG Li, FENG Zhe-Ling, WANG Yi-Tao, LIN Li-Gen* State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China Available online 20 Dec., 2017

[ABSTRACT] Pharmaceutical research has focused on the discovery and development of anticancer drugs. Clinical application of chemotherapy drugs is limited due to their severe side effects. In this regard, new naturally occurring anticancer drugs have gained increasing attention because of their potential effectiveness and safety. Fruits and vegetables are promising sources of anticancer remedy. Clausena (family Rutaceae) is a genus of flowering plants and includes several kinds of edible fruits and vegetables. Phytochemical and pharmacological studies show that carbazole alkaloids and coumarins from Clausena plants exhibit anticancer activity. This review summarizes research progresses made in the anticancer properties of plants belonging to Clausena; in particular, compounds with direct cytotoxicity, cell cycle arrest, apoptosis induction, and immune potentiation effects are discussed. This review reveals the potential use of plants from Clausena in preventing and treating cancer and provides a basis for development of relevant therapeutic agents. [KEY WORDS] Clausena; Anticancer; Carbazole alkaloids; Coumarins

[CLC Number] R284

[Document code] A

[Article ID] 2095-6975(2017)12-0881-08

Introduction Cancer is a leading cause of death worldwide. The World Health Organization (WHO) has reported that approximately 14.1 million new cases of cancer are diagnosed globally (not including skin cancer other than melanoma); cancer led to about 8.2 million human deaths (14.6%) in 2012 [1]. Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body [2]. Both external (tobacco, alcohol, chemicals, infectious agents, and radiation) and internal factors (hormones, immune conditions, inherited mutations, and mutations occurring in metabolism) can cause DNA mutation in normal cells, resulting in cancer initiation and development [3]. Chemotherapy is the most popular and widely accepted method for cancer treatment. However, clinical application of chemotherapy drugs is limited due to their [Received on] 1- Mar.-2017 [Research funding] This work is supported by the Macao Science and Technology Development Fund (No. 120/2013/A3) and the Research Fund of University of Macau (Nos. MYRG2015- 00153-ICMSQRCM and MYRG2017-00109-ICMS). [*Corresponding author] Tel: +853-88228041, Fax: +853-28841358; E-mail: [email protected]. These authors have no conflict of interest to declare. Published by Elsevier B.V. All rights reserved

unwanted adverse effects, such as hair loss, nausea, fatigue, and vomiting [4]. In this regard, scholars have proposed natural products as alternative treatment because of their potential effectiveness and safety [5]. In the past few decades, many studies were conducted to search for new cancer treatments from natural products [6-7]. As important parts of daily diet, fruits and vegetables supply a wide range of nutrients and provide a broad prospect for research and development of new anticancer drugs. Clausena, a genus of flowering plants in the family Rutaceae, includes shrubs and trees and is widely distributed in Africa, tropical and subtropical regions of Asia, Australia, and the Pacific islands [8]. Although the taxonomy of Clausena remains unclear, this genus is estimated to contain 15−30 species [8]. Thus far, only 14 species have been chemically or pharmacologically studied; those species include C. excavata, C. lansium, C. harmandiana, C. anisata, C. heptaphylla, C. emarginata, C. dunniana, C. indica, C. wallichii, C. anisum-olens, C. guillauminii, C. vestita, C. lenis, and C. pentaphylla. Clausena mainly consists of edible fruits and vegetables. The young leaves of C. excavata, C. guillauminii, C. harmandiana, and C. wallichii are popular vegetables in Thailand. Wampee (C. lansium) is a fruit widely distributed in China, Vietnam, the Philippines, Malaysia, and Indonesia [9]. The fruits of C. anisum-olens, C. excavata, and C. emarginata [9],

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are also popular in China and Southeast Asia. The major components in plants belonging to Clausena include carbazole alkaloids and coumarins, which exhibit potent anticancer activity in various cell models. However, the related research progress has not been summarized yet. Herein, we aim to provide a comprehensive review of the traditional use, phytochemical studies, and pharmacological investigations related to the anticancer properties of plants belonging to Clausena.

Ethnopharmacology and Traditional Uses of Plants from Clausena Many plants belonging to Clausena are used as folk medicines. The leaves of C. lansium are used for the treatment of cough, asthma, viral hepatitis, and dermatological and gastrointestinal diseases [9]. Different parts of this plant are also used as folk medicines for the treatment of acute and chronic viral hepatitis in China. The aerial parts of C. anisum-olens, a shrub that grows in Yunnan Province, China, are traditionally used to treat dysentery and arthritis [9-10]. C. excavata, commonly called “San Soak” in Thai, is a wild shrub widely distributed in South and Southeast Asia. Several parts of this species are used as traditional medicines for the treatment of cold, malaria, acquired immunodeficiency syndrome, dermatopathy, abdominal pain, and snake-bite in Thailand [9, 11]. C. anisata is widely used in West Africa to heal bacterial and fungal skin infections, including boils, ringworm, and eczema. C. emarginata, a bush widely distributed in the southern part of China, is used to treat cough, headache, gastrointestinal diseases, and rheumatic arthritis [9]. C. harmandiana is small evergreen tree or shrub, and several parts of this plant are used to treat stomach pains and headaches. The leaves and barks of C. lenis are used for treatment of dysentery and arthritis [12]. Many kinds of healthy food on market are derived from plants belonging to Clausena.

Phytochemical and Pharmacological Studies of Clausena Phytochemical investigations of plants belonging to Clausena have identified tens of structurally diverse and biologically active alkaloids and coumarins [13]. Alkaloids are categorized into carbazole, amide, and quinoline, of which carbazole alkaloids are the most abundant and typical components of plants from Clausena. Coumarins are categorized into furanocoumarins [14-16], pyranocoumarins [17-18], O-terpenoidal coumarins [11, 19], and dimeric coumarins [12, 20]. Few limonoids [21-23], peptide derivatives [24-25], and ring A-rearranged clerodane diterpenoids [26] are also identified from Clausena plants. The chemical components of plants from Clausena have been reviewed previously [11, 13, 27]. Modern pharmacological studies have shown that carbazole alkaloids and coumarins from Clausena plants exhibit various bioactivities, such as antimicrobial [28-30], anti-inflammation [31-33], anticancer [34-36], anti-oxidation [37-40] and anti-human immu-

nodeficiency virus (HIV) effects [41-42]. Particularly, the anticancer potential of these compounds has gained increasing research interest. The components of Clausena plants can inhibit tumor growth through direct cytotoxicity [42], induction of tumor cell apoptosis [34-36], and/or immune potentiation [38, 43]. Anticancer activity of fractions from Clausena plants Albaayit et al. have found that the chloroform and ethyl acetate extracts of C. excavata exhibit toxicity to HaCaT cells at 200 and 400 μg·mL−1, respectively [39]. The hot water extract, acetone extract, and folklore preparation of C. excavata are also assayed on mouse splenocyte proliferation. The results show that the hot water and acetone extracts exert potent inhibitory effects; in folk medicine, this plant is widely used as a remedy for patients with cancer in the eastern part of Thailand [39]. Prasad et al. have reported that the ethyl acetate fraction of C. lansium peel extracts exhibits stronger anticancer activities against human gastric carcinoma (SGC-7901), human hepatocellular liver carcinoma (HepG-2), and human lung adenocarcinoma (A-549) cancer cell lines than cisplatin, a conventional anticancer drug [40]. This study is the first report on anticancer activities of the C. lansium peel extract. Anticancer activity of carbazole alkaloids from Clausena plants Carbazoles are a class of tricyclic heteroaromatic alkaloids, with two benzene rings fused onto a pyrrole ring as the core structure. The medicinal functions of naturally occurring carbazoles have gained increasing attention due to their wide range of biological activities; carbazoles are regarded as a vital heterocyclic class of anticancer agents [44]. Some carbazoles with potent anticancer activity have undergone clinical trials. Patients enrolled in the trials have reported complications caused by multidrug resistance [44]. As such, few types of carbazoles have been approved for cancer therapy. Planar, polycyclic, and aromatic carbazoles exhibit anticancer activity through DNA intercalation or inhibition of DNA-dependent enzymes, such as telomerase and topoisomerase I/II [45]. As an important source of natural carbazole alkaloids, the plants of Clausena have been widely investigated; tens of anticancer carbazole alkaloids have been identified thus far (Table 1 and Fig. 1). In 2002, Cui et al. found that the alkaloid, 3-methylcarbazole (1) isolated from C. dunniana, exerted potent anti-proliferative activity in human fibrosarcoma HT-1080 cells, with IC50 value of 25 μg·mL−1 [34]. Murrayafoline A (11), bicyclomahanimbine (28), girinimbine (30), and mahanimbine (31) also induce M-phase cell cycle arrest and apoptosis in mouse tsFT210 cells [34]. These studies are the first report that carbazole alkaloids can be used as cell cycle inhibitors and apoptotic inducers. To search anticancer agents, Jiang et al. identified three carbazole alkaloids from the stems of C. lansium, 3-formylcarbazole(2),methyl carbazole-3-carboxylate (3), and 2-methoxy-1-(3-methyl-buten-1-yl)-9H-carbazole-3-carbalde hyde (20), which display potent cytotoxic activity against nonsmall lung carcinoma (H1299) and liver cancer (SMMC-7721) cells, with IC50 values ranging from 6.19 to 26.84 μg·mL–1 [46].

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Table 1 Anti-cancer carbazole alkaloids from Clausena plants R4

R3

R5

N H

R6

R2 R1

No

R1

R2

R3

R4

R5

R6

1

H

H

Me

H

H

H

3-Methylcarbazole

Name

Source

2

H

H

CHO

H

H

H

3-Formylcarbazole

C. lansium

[49]

3

H

H

COOMe

H

H

H

Methyl carbazole-3-carboxylate

C. lansium

[46, 57, 63]

4

H

H

CHO

H

OMe

H

Clauszoline K

C. harmandiana

[55]

5

H

H

COOH

OMe

H

H

6-Methoxy-9H-carbazole-3-carboxylic acid

C. lansium

[28]

6

H

OH

Me

H

H

H

2-Hydroxy-3-methylcarbazole

C. vestita

[57]

7

H

OH

CHO

H

H

H

Mukonal

C. harmandiana

[55]

8

OH

H

CHO

H

H

H

O-Demethylmurrayanine

C. excavata

[28]

C. dunniana

Ref [34]

9

OH

H

COOMe

H

H

H

Clausines E

C. excavata

[49, 53, 57, 64]

10

OMe

H

CHO

H

H

H

Murrayanine

C. excavata

[49]

11

OMe

H

CH3

H

H

H

Murrayafoline A

C. dunniana

[21, 34]

12

H

OH

COOMe

H

OMe

H

Clausine TY

C. excavata

[48]

13

H

OH

CHO

H

OH

H

Clausine O

C. vestita

14

H

OH

CHO

H

OMe

H

7-Methoxymukonal

C. harmandiana

[55, 57]

15

H

OMe

CHO

H

OMe

H

Clauszoline J

C. excavata

[49, 57]

[57]

16

OH

H

CHO

OH

H

H

Clausine Z

C. vestita

[57]

17

OH

CHO

prenyl

H

H

H

Clausine D

C. excavata

[28]

18

OMe

OH

CHO

H

H

H

Claulansine N

C. lansium

[63]

19

OMe

H

H

H

C. anisata

[54]

20

prenyl OMe

CHO

H

H

H

C. lansium

[46]

21

prenyl

OH

CHO

H

H

H

Clausamine D 2-Methoxy-1-(3-methyl-buten-1-yl)9H-carbazole-3-carbaldehyde Heptaphylline

C. harmandiana

[56]

22

H

OH

CHO

OMe

H

23

H

OH

CHO

H

prenyl

OH Excavatine A

C. excavata

[52]

24

prenyl

OH

CHO

H

H

OH Heptazoline

C. harmandiana

[55]

25

prenyl

OH

CHO

H

OMe

C. harmandiana

[56]

COOMe prenyl

OMe Clausine B

H

C. wallichii, C. excavata

7-Methoxyheptaphylline

In 2014, several carbazole alkaloids were identified from the stems of C. lansium. Among those compounds, 6-methoxy9H-carbazole-3-carboxylic acid (5) exhibits moderate cytotoxicity against MCF-7, H1299 and SMMC-7721 tumor cell lines; and O-demethylmurrayanine (8) and clausine D (17) possess strong cytotoxicity against MCF-7 and SMMC-7721 cells, with IC50 values of 2.63–7.59 mg·mL–1 [28]. In a chemical isolation of the roots of C. lansium, mafaicheenamine E (29) was found with cytotoxicity against MCF-7 cells with IC50 value of 3.1 μg·mL–1; hence, mafaicheenamine E (29) could be further studied considering its selective anticancer activity against MCF-7 cells [47]. Different extracts of C. excavata show anti-proliferative effects. Taufiq-Yap et al. have isolated a carbazole alkaloid, namely clausine TY (12), from the ethyl acetate extract of the stem barks of C. excavata; this compound shows significant cytotoxicity against CEM-SS cells, with IC50 value of 44.80 μg·mL–1 [48]. In 2012, Sripisut et al. investigated the roots of C. excavata and found that clauszoline J (15) pos-

[13, 58]

sessed cytotoxicity activity against classic small cell lung cancer cell line (NCI-H187); moreover, murrayanine (10) exhibited cytotoxicity against KB, MCF-7 and NCI-H187 cell lines [49]. Clausenamine A (32) is a dimeric carbazole alkaloid isolated from the stems and root backs of C. excavata. Zhang et al. have synthesized this compound and reported its anti-proliferative and cytotoxic effects against cancer cells [50]. In 2009, Zain et al. found that clausine B (22), an alkaloid isolated from the stem bark of C. excavata, exhibited potent activity against four cancer cell lines, with IC50 values being 21.50 μg·mL–1 (MDA-MB-231), 22.90 μg·mL–1 (human cervical carcinoma, HeLa), 27.00 μg·mL–1 (CAOV3), and 28.94 μg·mL–1 (human hepatocellular liver carcinoma, HepG2), respectively [51]. In 2013, Peng et al. found that excavatine A (23) from C. excavata exhibited cytotoxicity against human clung adenocarcinoma epithelial (A549) and HeLa cell lines, with IC50 values being 5.25 and 1.91 μg·mL–1, respectively [52]. Additionally, clausine E (9) showed moderate topoisomerase II inhibitory effect at 50 μmol·L–1 [53].

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Fig. 1 Anticancer carbazole alkaloids from Clausena plants

Ito et al. have identified several carbazole alkaloids from the branches of C. anisata; of those alkaloids, clausamine D (17) inhibits Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells [54]. In Thongthoom and his colleagues’ study, a series of carbazole alkaloids were identified from C. harmandiana; among them, 7-methoxymukonal (14) showed strong cytotoxicity against MCF-7 and KB cell lines, with IC50 values of 2.21 and 1.74 μg·mL–1, respectively; heptaphylline (21) and 7-methoxyheptaphylline (25) showed strong cytotoxicity against NCI-H187 and KB cell lines, with IC50 values ranging from 1.3 to 2.7 μmol·L−1; and heptazoline (24) exhibited moderate cytotoxicity against MCF-7 cells [55]. Songsiang et al. have isolated five alkaloids from the roots of C. harmandiana; among them, clauszoline K (4) and mukonal (7) show strong cytotoxicity against NCI-H187 and KB cell lines, with IC50 values ranging from 1.3 to 2.7 μmol·L–1 [56]. In 2012, Lin et al. identified 16 alkaloids from C. vestita, and found that clauszoline K (4), 2-hydroxy-3-methylcarbazole (6), clausine E (9), clausine O (13), 7-methoxymukonal (14), clauszoline J (15), and clausine Z (16) possessed cytotoxic activity against HepG2 cells [57]. Among these compounds, clausine E (9) exhibited an evident growth inhibitory activity by inducing cell cycle arrest in the S and G2/M phases. Clausine E-treated HepG2 cells showed considerable morphologic change with decreased F-actin staining and RhoA activity and inhibited phosphorylation of PKCδ (protein kinase C δ, Ser643). Maneerat et al. have isolated clausenawalline F (33), a carbazole alkaloid, from the roots of C. wallichii; this compound shows strong cytotoxicity against oral cavity cancer

(KB) and small-cell lung cancer (NCI-H187), with IC50 values being 10.2 and 4.5 μmol·L−1, respectively [58]. Clausenawalline A (34), a dimeric carbazole alkaloid isolated from the roots of C. wallichii, shows cytotoxicity against three human cancer cell lines, KB (IC50 7.87 μg·mL–1), MCF-7 (IC50 25.43 μg·mL–1), and NCI-H187 (IC50 10.97 μg·mL–1) [59]. Auranwiwat et al. have isolated fluroclausine A (26) and clauraila D (27) from the roots of C. guillauminii; fluroclausine A (26) shows strong cytotoxic activity against KB cells, with an IC50 value of 1.35 μg·mL–1 [60]. In summary, 34 carbazole alkaloids from Clausena species have been discovered to possess anticancer activities. Most of these alkaloids are isolated from Clausena species used as vegetables or fruits. Amide alkaloids, which are also identified from Clausena plants, have not been reported to possess anticancer activity. Carbazoles are a vital heterocyclic class of anticancer agents; as such, Clausena plants are an important source of new scaffolds and building blocks for semi-synthesis of carbazoles. Further studies should be conducted to identify more carbazole alkaloids with potent anticancer effect even when administered at low amounts. Additionally, sensitive and efficient bioassays should be designed to screen naturally occurring carbazole alkaloids with anticancer property. Anticancer activity of coumarins from Clausena plants Coumarins are fused benzene and pyrone ring systems with diverse biological activities. Coumarins possess immeasurable anticancer potential and elicit minimal side effects depending on substitutions on the basic nucleus [61]. As the major constituents of Clausena plants, coumarins with anticancer property have become the focus of research for decades (Table 2 and Fig. 2).

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Table 2 Anti-cancer coumarins from Clausena plants OR 1 R3 O

O

O

R2

No

R1

R2

R3

Name

Source

Ref

35

Me

H

H

xanthoxyletin

C. harmandiana

[42, 68]

36

H

-C(CH3)2CH=CH2

H

nordentatin

C. excavata

[42, 52]

37

H

-C(CH3)2CH=CH2

-C(CH3)2CH=CH2

clausarin

C. excavata

[42]

38

Me

-C(CH3)2CH=CH2

H

dentatin

C. excavata

[38,42, 65]

Name

Source

Ref

clauslactone A

C. excavata

[17]

clauslactone B

C. excavata

[17]

clauslactone C

C. excavata

[17]

clauslactone D

C. excavata

[17]

clauslactone E

C. excavata

[17]

R2

Name

Source

Ref

H

clauslactone F

C. excavata

[17]

H

clauslactone H

C. excavata

[17]

H

clauslactone I

C. excavata

[17]

H

clauslactone J

C. excavata

[17]

OMe

scopoletin

C. excavata

[52]

O

O

O

O R

No

R O OH O

43

O OH O

44

OH O

OH O

45

OH OH O

OH O

46

OH

O O

47

O O

O

O

OH R2 R1O

No

R1

O

O

O O

48 O

O O

49 O

OH

O O

50

OH OH O

O

51

OH

O

52

H

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and C. lansium have exhibited anticancer activities. Further studies should be conducted to identify other coumarins from other species of Clausena.

Conclusion A considerable amount of studies have been conducted to investigate the chemical constituents and anticancer properties of Clausena plants. A total of 34 carbazole alkaloids and 18 coumarins identified from Clausena plants exhibit anticancer activities. In this review, we summarized the anticancer activity of eleven species of genus Clausena. This review provides a basis for further structure modification and medicinal investigations. So far, most studies have only focused on in vitro cell models. No direct in vivo study or clinic study has been conducted to validate the anticancer property of fractions, alkaloids and coumarins from Clausena plants. Hence, the feasibility of compounds from Clausena plants as drug candidates or lead compounds for treatment of cancer must be confirmed. Further pharmacological, chemical, and toxicological studies should be conducted to validate the therapeutic potential of Clausena plants.

Fig. 2 Anticancer coumarins from Clausena plants

In 2009, Su et al. isolated three compounds, nordentatin (36), clausarin (37), and clausenidin (39), from the medicinal plant C. excavata [42]. These compounds showed cytotoxic activity against four human cancer cell lines (A549, MCF-7, KB, and KB-VIN); of which, clausarin (37) showed potent cytotoxic activity with EC50 values of 2.98, 7.96, 1.61, and 1.59 μg·mL–1, respectively [42]. Sripisut et al. have found that xanthoxyletin (35), nordentatin (36), dentatin (38), and clausenidin (39) from the roots of C. excavata, showed cytotoxic activity against NCI-H187 cell line, with IC50 values of 35.54, 7.10, 15.92, and 8.63 μg·mL–1, respectively [49]. Moreover, scopoletin (52) is found to possess cytotoxic activity against MCF-7 cell line with IC50 value of 17.09 μg·mL–1 [49]. Dentatin (38), a compound isolated from the roots of C. excavata, induces apoptosis via the mitochondrial mediated signaling [62], nuclear factor κ-B (NF-κB) signaling and G0/G1 cell cycle arrest [35]. Ito et al. have found nine furanocoumarins, clausalctones A−F, H−J (43−51), from the leaves of C. excavata; these compounds exhibitinhibitory activity against TPA-induced EBV-EA activation in Raji cells [14]. Jiang et al. have identified 9-[3-methyl-4-(4-methyl-5oxo-tetrapydro-furan-2-yl)-but-2-enyloxy]-furo[3, 2-g]chromen7-one (41) from C. lansium; this compound show moderate cytotoxicity against MCF-7, H1299, and SMMC-7721 cancer cell lines [28]. The same group has also identified 8-geranyloxypsolaren (42) from the stems of C. lansium; this compound shows weak cytotoxicity in the tumor cell line [46]. 8-Hydroxylpsoralen (40) is identified from the extract of C. lansium fruit and shows potent proliferation inhibitory activity against HepG2, A549, and Hela cell lines. In summary, 18 coumarins identified from C. excavata

Abbreviation WHO HIV EBV-EA TPA PKCδ KB NF-κB

Full name World Health Organization anti-human immunodeficiency virus Epstein-Barr virus early antigen 12-O-tetradecanoylphorbol-13-acetate protein kinase C δ cavity cancer nuclear factor κ-B

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Cite this article as: HUANG Li, FENG Zhe-Ling, WANG Yi-Tao, LIN Li-Gen. Anticancer carbazole alkaloids and coumarins from Clausena plants: A review [J]. Chin J Nat Med, 2017, 15(12): 881-888.

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