Chapter 27. New Developments in Natural Products of Medicinal Interest

ANNUAL REPORTS IN MEDICINAL CHEMISTRY-IS

Chapter 27.

255 -

New Developments in Natural Products of Medicinal Interest

Lester A. Hitscher and A l i Al-Shamma, Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045 Introduction - In 1978, 25% of the 200 most frequently prescribed drugs in the USA were of direct natural provenance or derived therefrom by a few simple chemical steps. Despite this, except for antibiotics and antitumor agents from microorganisms or from the sea, such work has been relatively neglected in recent years in this country. Recent advances in chromatography and in microspectrometric methods of structure analysis coupled with an increased reliance upon bioassay-directed fractionation present unusual opportunities for progress today. This, combined with a renewed enthusiasm for novel structures as potential pharmacodynamic agents, provided the inspiration for this review. Primary emphasis has been placed upon work appearing in the last 3 years in which the structure of the active agent is known. Because of adequate coverage elsewhere in this volume, hormones, antitumor agents and antibiotics from traditional sources have not been included. Even sorthe remaining coverage is selective because of space consideration. Natural products are the end result of enzymatic manipulation from normal primary metabolic pools and, as such, are inherently more likely to interact successfully with other biopolyrners, such as receptors, than many of the compounds produced as the result of purely chemical imagination. Because bioactive natural products have been elaborated evolutionarily for other purposes, the average natural product is unlikely to be a clinically useful drug in its own right but rather serves as a chemical clue which, using modern principles of drug design and lead refinement, can lead to exciting new series for study and clinical development. Non-Steroidal Antiinflammatory Agents - A number of leads, usually with inadequate pharmacological work-up, are available from higher plants. These compounds are of diverse structure,including terpenes (barbatosides A and B (L) from Dianthus Barbatus,l helenalin ( 2 ) from Eupatorium phenols (clitoriacetal formosannum,2 (-)-a-bisabolol (3) from camomile)? (4) from Clitoria macro h lla),T acids (isoferulic acid (5) from CTmicifuga dahurica) and alkaloids (taspine (5) fr'om Croton lechleri6 and ephedroxane (L) from Ephedra intermedia) .7 It is interesting to note that the majority of these leads enjoyed _ _ a fol.kloric reputation prior to scientific siudy. It is also interesting that ephedroxane was a well-known synthetic chemical prior to its discovery using bioassaydirected fractionation methods. From the limited amount of testing data available, taspine (5) appears to be the most potent of this group of agents, being 3-4 times more active orally than phenylbutazone ~6 caragenin-induced pedal edema. The use of a-methylenelactonic sesquias antiinflammatory agents would seem terpenes, such as helenalin to be precluded by their well-known activity as allergic contact dermatitis causing agents .a

+

(z),

CopyriJllO 1980 by Academic Prar. Inc ,411 ri&u of rcprduaion in m y form m r d . ISBN 0.12-0405IM

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Sect. VI - Topics in Chemistry and Drug Design Renfroe, Ed.

Antabuse-like Activity - Given the chronic problem many nations face with alcohol abuse and recent problems associated with the use of disulfurarn, the finding that coprine (2). isolated from the inky cap mushroom Coprinus atramentarius, also interferes with alcohol dehydrogenase mediated alcohol metabolism has attracted considerable interest.9,lO

H02C

%HM

CHO OH

HO

OH CH3

(8)

CHo

to

CO2CH3

H3C (9)

OH

% ' H3

(lo)

Antifertility Agents - Higher plant extracts frequently possess antifertility activity.11~12 Recently, great interest was aroused by reports emanating from The Peoples Republic of China that gossypol @), from cotton seed oil and from Thespesia populnea, inhibits sperm formation 4-5 weeks after oral administration is begun, without depressing testosterone levels. Use, therefore, as a male contraceptive is contemplated.13 Aristolic acid and methyl aristolate (10) from the roots of Aristolochia indica show oral abortificient activity in ex2erimental animals. It is more effective in mice than in rabbits34 Antiulcer - Recent papers have drawn attention to the potential antiulcer activity of terpenes or widely different molecular complexity. A Thai medicinal plant, Croton sublyratus, contains (E,Z,E)-7-hydroxymethyl3,11,15-trimethy1-2,6,10,14-hexadecatetraen-l-ol (18-hydroxygenanylgeranol, 11)which is potent against rat Shay-ulcer and reserpine-induced ulcer in mice.15 The diterpenes, plaunol A (2) and B from the

(z),

Chap. 27

New Developments in Natural Products Mitscher, Al-Shamma

same species possess the same type of activity. ably more active than ~.16

257

Plaunol B is consider-

Cardiovascular Agents - It is generally accepted that adenosine plays an important role in the regulation of coronary blood flow even though the precise mechanism is not clear.17 Therefore it is interesting to note that the major asystolic agents in the marine sponge Dashychakina cyathina turn out to be adenosine and 2'-deoxyadenosine.l8 The well-known indole alkaloids hamine (141, harmaline (15)and harmalol (16)from Peganum harmala have profound effects upon the heard9 and the benzyltetrahydroisoquinoline alkaloid higenamine (17). from Aconitum japonicum, shows , from Coleus chronotropic activity.20 A diterpene, forskolin (2) forskolilii, has hypotensive activity as a consequence of its potent positive inotropic activity and vasodilator properties. 21

-

CNS Depressants A lignan, (+)-nortrachelogenin (E),from Wikstroemia indica prolongs thiopental slee ing-time in mice and antagonizes methamphetamine action in rabbits.2q The terpenes 8-eudesmol (2) and were isolated from Atractylodes lancea, A. ovata and A. hinesol (2) Japonica and proved to be the weakly potent CNS depressant agents in the an isolation crude drug "Zhu". 23 Among the alkaloids, gentianine (g), artifact derived from swertiamarin in studies upon Swertia japonica, shows moderate CNS depressant activity as-well as antiulcerogenic activity when given p.0. or i.d. to mice.L4 Dactylyne (23), an unusual

CH3

Q m

HO

H m

O

H

N

%

0

%

0

OH

halogenated acetylene derivative isolated from the sea hare, Aplysia dactylomela, significantly potentiates pentobarbital sleep time when given i . p . t o mice at 25 mg/k This was traced to inhibition of the metabolism of the barbiturate.5$ Finally, the xanthone diglucoside, mangostin-3,6-di-~-glucoside (24) isolated from Garcinia man ostana (mango) depresses CNS function as well as raises blood pressure

-

+

Diuretic Pepstatin (g), an inhibitor of several acid proteases, has been investigated as a potential antiulcer and antihypertensive agent. Recently, it has been shown to be strongly diuretic at 80 mg/kg in mice when given in a single subcutaneous injection. This may be due to aldosterone antagonism by an indirect mechanism involving antagonism of

258

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Topics in Chemistry and Drug Design Renfroe, Ed.

renin.27 It is interesting t o note that pepstatin was isolated from the fermentation products of a Streptomycete as part of a productive program which searches for pharmacodynamic agents other than antibiotics and antitumor agents from microorganisms.

Enzyme Inhibitors - Fermentation products of Streptomycetes continue to be fruitful sources of specific enzyme inhibitors of potential clinical value. One of the more important is gabaculine (g), from to ocaensis an inhibitor of the inhibitory neurotransmitter GABA.28 (27) was isolated from nigellus and -&ylacetaldoxime shown to inhibit B-galatosidase, a widely distributed enzyme of uncertain biological function.29

e.

e.

-

Hypoglycemic Agents Carboxyatractylate, 28, (ID5o = 10.7 mg/kg i.p. in mice), was found to be responsible f8r the hypoglycemic action of cocklebur extracts (Xanthium strumarium).

-

Hypotensive Agents Many alkaloids have shown hypotensive activity over the years, and an intensive investi ation of the genus Thalictrum h a s added many new agents to the li~t.3?-~~A number of these agents, notably thaliglucinone also possess antimicrobial activity. The hypotensive alkaloids recently characterized are adiantifoline (2) and thaliadamine (30) from Thalictrum minus;3l thaliracebine (2) and thalirabine (32) from a second study of T. minus;32 thalicarpine thalidasine , 2-methylthalicberine (7L)xlrugosamine (36), thaliglucinone (37) and thalphenine (38) from r e v ~ l u t u m ;thaliglucinone ~~ (37) from T. longistylum;3' staurosporine (2)from a Streptomyces and B (2)from Ephedra vulgaris.36 s p e ~ i e s ; ~ ~ aephadrine nd A (9)

(x),

(z)

r.

(z),

Streptomyces species generally do not contain alkaloids in the classical sense. Staurosporine (39) is exceptional, and,in addition to its antimicrobial activity, is also strongly antihypertensive. Ephedra vulgaris has been extensively examined, yet continues to provide new alkaloids among which

Chap. 27

New Developments in Natural Products Mitscher, A l - S h a m

ephadrine A

(40)

is significantly hypotensive i . v . in mice (1.5-1.8

CH30

( 2 9 ) . R.GH2 (30); R=H "

259 mg/kg).

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Sect. VI - Topics in Chemistry and Drug Design Renfroe, Ed.

Spasmolytic - Daidzein (g), an isoflavone from Pueraria tuberosa and other plants, shows about a third of the spasmolytic effect of papaverine on mouse small intestine preparations,37 and the more complex terpenoidal coumarins, clausmarins A and B (isomers at C2, 43) from Clausena pentaphylla, are potent spasmolytic agents in experimental animals.38 Hypocholesterolemic Agents - Totarol (*), from Thujopsis dolabrata, reduces blood levels about 27% when added at about 0.1% to a cholesterol enriched diet and fed to rats.39 Several other terpenes are active -notably abietic acid (45) presumably all by interfering with cholesterol absorption from the intestine. Bre nin G and B, glycosides of breynogenin (46) of Breynia officinalis,4(K were effective in rats when The fungus, given Lp. but they were also rather toxic (0.2-0.5 mg/kg). P thium ultimum produced an agent which interfered with hepatic choleski-sis without hepatomegly Fractionation showed this agent to be citrinin (z>,41 well known as a toxic antibiotic but not previously known to have this activity. A similar investigation of the metabolites of Penicillium citrinum led to three related metabolites, ML-236A (g), ML-236B (49) and ML-236C of which B is the most potent inhibitor of in vitro cholesterol biosynthesis. Compound B is also active in r a t Z r

--

.

(z),

(z),

Antimuscarinics - Gephrytoxin an acetylenic alkaloid from the skin of the Colombian frog Dendrobates histrionicus, joins the group of exotic neuroactive natural products from neotropical frog extracts which possess relatively potent muscarinic antagonist properties .43

Chap. 27

New Developments in Natural Products Mitscher, Al-Shamma

261

Immunosuppressive Agents - K-76 (52) is a compliment inhibitor from Stachybotrys complimenti which might be useful in immune-complex diseases and, indeed, appears to improve the symptoms of experimental glomerulonephritis. 44 Gamma-L-Glutaminyl-4-hydroxybenzene (53)was isolated from the edible mushroom Psalliota bisporous45 and shown to inhibit DNA synthesis in human lymphocytes stimulated with phytohemagglutinin. It is active at 4 mcg/ml, not very toxic (LDso = 5 gfkg), and is now being tested for its ability to delay skin homograft rejection. Antifungal Agents from Higher Plants - Antifungal agents are widely distributed among the higher plants, especially agents elaborated in response to fungal attack (phytoalexins -- suicide metabolites). This accounts for the relative resistance many plants exhibit to fungal invasion. Unfortunately, few of these agents have been tested against human pathogens and almost none have been studied in animal models.

HO" HO..

(52) (53)

NH2

H O?

(54)

carpesiolin (66) from Carpesium abrotanoides;52 Ptilonia metabolite (67) from Ptiloniaaustralasica;3 3 and uliginosin A (68)from Hypericum uliginosum.34 Tryptanthrin has a folkloric reputation in Taiwan and is active against atheletess foot infections.

OH OE

4-l

0

A

, C=H

c 'B

, A=H

( 5 8 ) , A=H,

B=OCH3,

C=CH2

( 6 2 ) , A=B=E=H,

C=OH,

D= C H 2

262 -

Sect. VI

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Topics in Chemistry and Drug Design Renfroe, Ed.

(67)

(66

(68)

Antiviral Agents From Higher Plants - Antiviral activity is not often reported from higher plants and is rarely pursued beyond the in vitro stage. Recently, 10-methoxycamptothecin (69),from Ophiorrhiza mun 0 8 , has been shown to inhibit herpes virus in xtro,55 and gossypol&and its less toxic deformylation product (2). from the pigment 61 nd of cotton seed, have shown activity in mice against influenza virus. 5% Compound 2 had previously been known as an antileukemic agent.57 R

OH

R

RSHO (69)

\.'

R

A

R=H

Antibacterial Agents from Higher Plants - Antibacterial compounds are widely distributed in the plant kingdom.58 Unfortunately, the agents are rarely evaluated in The active agents are often new to the literature but usually belong to series structurally familiar to natural products chemists. The mildly antiseptic activity of alcohols (such as santolinol (72,from Artemesia herba-alba59) and simple phenolics (atylosol (73) from Atylosia t r m p i s i f e r i c acid (74)from Chamaecyparis pisifera [the carboxy group is incidental since ferruginol 62 (75) is more potent than 741fi1 xylopic acid (76) from Xylopia aethiopica, vzious xanthones from Canscora decussata,of which 77 and 78 are 0.1 x as active as streptomycin Mycobacterium tuberculosis;63 f lavanoids ; chalcones from Uvaria chamae, of which uvaretin (2) and dichamanetin (80) are representative, potent, and broad spectrud'i; and the flavanone glabrol ( g ) the , most potent principal of Glycyrrhiza glabra65), has been known for a long time. The more complex members are more selective and more potent suggesting that further investigation would be rewarding. A number of alkaloids, such as the bisbenzylisoquinolines hernandezine (82), thalidezine (83) and thalistyline (84) from Thalictrum odocar um66 and the isolation artifacts from Hunnemanxa fumariaefolia (t e apparent prodrug pseudoalcoholates (85, 86) and nitrile (87) of sanguinarine67). are broad spectrum and representative. Compounds 85-87 are dramatically more potent than sanguinarine itself. Rounding out this group is a sentimental favorite, louisfieserone (88) from Indigofera suffruticosa.68

w.

+

Chap. 27

New Developments in Natural Products Mitscher, A l - S h a m

HP

&Zc %02H

(73)

HO

HO

(77 HO

OR

HO

263

Sect. VI - Topics in Chemistry and Drug Design Renfroe, Ed.

264

The antipseudomonal activity of ferruginol and xylopic acid, the antitubercular activity of uvaretin and the canscora xanthones and the potency of glabrol are of particular interest. Miscellaneous - A heterogeneous pharmacological and structural group remains. Unfortunately, spatial restrictions prevent a detailed discussion of these compounds. Several of the more interesting substances falling into this category show promise of opening new areas of investigation, such as, for example, sclerosporin (97) and trigonelline (92). Reason for Interest or Pharmacological Action

Name

Source

Insecticide Insecticide Piscicidal Antimitotic Hormone Sweetening Agent Sweetening Agent Sweetening Agent Plant Growth Regulator Sporogenic in Fungi Antihepatatic Agent Chiral Prostaglandin Synthon Chiral Prostaglandin Synthon Adriamycin synthon

wilfordine (2) helicoside H3 (90) obovatin (91) trigonelline (92) stevioside (93) rebaudioside A ( 9 4 ) dulcoside A (95)hydroxyencomicacid sclerosporin (97) unnamed (98) aucubin (2)

Euonymous alatus69

terrein

(96)

(100)

aloe-emodin

(101)

Stevia rebaudiana74 Stevia rebaudiana75 -, Cattleya trianaeifb Sclerotina fruiticola7 7 Fructus schizandraelg Aucuba japonica 1 9 Aspergillus fischerii80

qco2 Aloe sp.81

-

I

nu 4

R ~ - D - g l u c o S y l ( l 2)-@-D-gl~coSyl R- -D-glucoSyl(l:2)-6-D-g1~~0~y1(1,3) -@-D-glucosyl (95 ), R$-D-glucosyl

Chap. 27

New Developments in Natural Products

lfitscher, Al-Shamma

265

References 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.

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of N a t u r a l P r o d u c t s , 1.H-,

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- 66, - 66. -.

=.

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59,

m. m.

-.,

z.,

-.

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u.,11. u,

%.

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wid,

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266 44. 45.

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- Topics in Chemistry and Drug Design

H. Kaise. M. S h i n o h a r a . W. Miyazaki. T. Izawa. Y. Nakano, M. Sugawara, K . S u g i u r a and K. S a s a k i . J . Chem. SOC., Chem. Commun., 726 (1979). T. Mouri. T. M u T a h E H T a y a m a . S. T s u t s u i , T. Kurokawa, Y. S h i b a t a . N. I s h i d a , S. Kakimoto, F. Asakura, H. Shirahama and T. Matsumoto, 2179

&. w. =..

.-N.W. P r e s t o n . 11978).-

2.

16,

- I

46. 47. 48.

Renfroe, Ed.

Phytochem.. 143 (1977). R.L. Lyne and L.J. M u l h e i r n , L e t t e r s , 3127 (1978). M. T a k a s u g i , S. Nagao. S. Ueno, T. Masamune, A. S h i r a t a and K . T a k a h a s h i . L e t t e r s . 1239 (1978); M. T a k a s u g i . S. Nagao and T. b s a m u n e , L e t t e r s . 797

x.

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