Chapter 12
Antineoplastic Agents and Their Analogues from Chinese Traditional Medicine Kuo-Hsiung Lee Natural Products Laboratory, Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599 Cytotoxic antitumor principles from Chinese traditional medicines, plant materials, and their semi-synthetic analogs are reviewed with emphasis on those discovered in the author's laboratory. The active compounds include sesquiterpene lactones, diterpenes, quassinoids, triterpenes, alkaloids, quinones, diamides, coumarins, flavonoids, lignans, macrolides, polyacetylenes, polyphenols, and styrylpyrones, as well as their derivatives and analogs. The structure-activity relationships and mechanism of action studies among these compounds are discussed wherever feasible. Chinese traditional medicines have been used in the treatment of cancer for centuries, but only recently has a systematic effort been made to isolate and characterize the active principles from their antitumor-active extracts. The progress made during the past two decades in the discovery and development of numerous such cytotoxic antitumor agents and their analogs has beenreviewed(7-8). Studies on Chinese plant-derived antineoplastic agents and their analogs are proceeding in many laboratories. However, to limit the scope of the present discussion, this review will deal mainly with the work carried out in the author's laboratory, especially on those compounds discovered recendy. Chinese Plant-Derived Antineoplastic Agents and Their Analogs in Clinical Use, Clinical Trials, and Under Development Several clinically useful anticancer drugs and their analogs discovered and developed initially in the U.S. and in other countries are currently also used in China as the sources of these drugs arereadilyavailable there. These include those used in the U.S., such as the Catharanthus alkaloids, vinblastine (1) and vincristine (2), and their analog, vindesine (3) (3, 9-72), and the podophyllotoxin-derived lignan glycosides, etoposide (4) and tenyposide (5) (3, 73-75). Other anticancer drugs used in China include 10-hydroxycamptothecin (6) (3, 5, 76, 77), homoharringtonine (7) (3, 18-20), monocrotaline (8) (3, 7, 27), lycobetaine (9) (3, 5, 8), colchicinamide (10) (3, 22), d-tetrandrine (11) (3, 2224), (-)-sophocarpine (12) (3, 8, 25), indirubin (13) and its derivative N,N' -dimethylindirubin (14), and N-methylindirubin oxime (15) (3, 5, 7, 26), curzerenone (16) (3, 4, 6, 27), curcumol (17) (4, 7), curdione (18) (4, 7), oridonin (19) (3, 4, 7, 28, 29), and gossypol (20) (3, 4 7, 8). Compounds 6, 7, 8, 11, 12, and 16-20 were initially discovered in the U.S. (6, 7, 11, and 20), y
0097-6156/93/0534-0170$06.25/0 © 1993 American Chemical Society
LEE
111
Antineoplastic Agents from Chinese Traditional Medicine
1, Vinblastine (Velban): R = C H , x
3
R = COOCH3, R = OAc 2
3
2, Vincristine (Oncovin): R = CHO, x
R = COOCH3, R = OAc 2
4, Etoposide: R =
HO^j-O
q
3
3, Vindesine: R = C H , R = CONH , R = OH x
2
H
3
2
OH
1
3
5, Teniposide: R =
— OH I
25, R = R2
R3
6, 10-Hydroxycamptothecin: R OH, R = R = H 21, Camptothecin: Rj R R — H 22, Hycamptamine: R = OH, R = CH N(CH ) , R =H 23, 9-Aminocamptothecin: R = OH, R = N H , R = H 24, CPT-11: 1 =
2
=
h
~ 0 ~
n
h
2
*
H
C
26, R = N H — C N
3
=
2
n
27, R =
N H —
N
° 2
3
x
2
2
3
2
28, R =
3
x
2
R = x
R
= 2
2
OCO-N
H, R
= 3
3
)—N
CH CH 2
y • HC1
29, R = N H — C O O C H z C H a 30, R =
3
"OCH3
7, Homoharringtonine
8, Monocrotaline
1
172
HUMAN MEDICINAL AGENTS FROM PLANTS
Australia (8), and Japan (11, 12, 18, and 19), respectively, but were first introduced into the clinic as anticancer drugs in China. Compounds 9,10,13,14, and 15 originated in China. A discussion on the major uses of these compounds has been included in a recent review (5) and is briefly summarized in Table I. Modification and analog development of camptothecin (21) and etoposide (4) aimed at producing improved drug candidates are of current interest Derivatives of Camptothecin. With the recent discovery of 21 and 6 as potent inhibitors of DNA topoisomerase I (30, 57), their derivatives, such as hycamptamine (22) (52), 9-aminocamptothecin (23) (55), and CPT-11 (24) (34), are being tested clinically as anticancer drugs (35) against colon and other cancers in Europe, the U.S.A., and Japan, respectively. Analogs of Etoposide. The podophyllotoxin-derived etoposide (4) and tenyposide (5) are effective anticancer drugs for the treatment of small-cell lung and testicular cancers, as well as lymphoma and leukemia (14, 15). There is evidence to suggest that these drugs block the catalytic activity of DNA topoisomerase II by stabilizing an enzyme-DNA complex in which the DNA is cleaved and linked covalently to the enzyme (36-38). It is possible to associate the cytotoxicity of 4 and 5 with the phenoxy free radical and its resulting ortho-qumone species formed by the biological oxidation of these drugs (39,40). The ortho-qwnone could cleave DNA if it forms metal complexes with Ca2+ and Fe3+ ions (41). Metabolic activation of 4 is believed to produce the phenoxy free radical and ortho-qmnonc derivatives of 4. This is because 4 as an alkylating species could bind to critically important cellular macromolecules causing dysfunction and, subsequently, cell death (42, 43). Recent studies in the author's laboratory involving the replacement of the 4p-sugar moiety with 4p-arylamino groups have yielded several compounds (2530) which were 5- to 10-fold more potent than 4 as inhibitors of DNA topoisomerase n in vitro. All of these compounds (25-30) could generate the same amount or more protein-linked DNA breaks in cells than 4 at 1-20 pM. In addition, these new compounds were cytotoxic not only to KB cells but also to their 4resistant and vincristine(2)-resistant variants which showed decreased cellular uptake of 4 and a decrease in DNA topoisomerase II content or overexpression of the MDR1 phenotype (44-46). Further development of these compounds for clinical trials as anticancer drug candidates is in progress. Chinese Plant-Derived Antineoplastic Agents and Their Analogs Discovered in the Author's Laboratory Bioassay-directed isolation and characterization of potent cytotoxic antitumor agents and analogs from Chinese medicinal plants has been one of our research objectives over the past two decades. This program has led to the identification of numerous new leads for further development as anticancer drugs. Recently, we have discovered more than 50 such compounds which are of interest to the U.S. National Cancer Institute (NCI). They are currently undergoing NCI's detailed evaluation as potential new anticancer agents. The key to the success for new drug discovery is the proper selection of a bioassay method. Previously in the 1970's and early 1980's, we used NCI's in-vitro KB and in-vivo P-388 as the prescreen methods (47) to detect potential cytotoxic antileukemic agents. We have recently also used NCI's expanded protocol (48, 49) to include several disease-oriented human cancer cell lines, such as A-549 (lung carcinoma), HCT-8 (ileocecal adenocarcinoma), MCF-7 (breast adenocarcinoma), and RPMI-7951 (melanoma) in our routine screening program aimed at discovering agents which might be active against slowly
12. LEE
Antineoplastic Agents from Chinese Traditional Medicine Table I: Major Uses of Compounds 1-21
Compounds
Major Uses
1 (Vinblastine)
Hodgkin's disease
2 (Vincristine)
Acute childhood leukemia
3 (Vindesine)
Adult nonlymphocytic leukemia, acute childhood lymphocytic leukemia, Hodgkin's disease, and malignant melanoma
4 (Etoposide)
Small cell lung cancer, testicular cancer, lymphoma, and leukemia
5 (Teniposide)
Acute lymphocytic leukemia, childhood neroblastoma, adult nonHodgkin's lymphoma and brain tumors
6 (10-hydroxycamptothecin)
Cancers of liver, head, and neck
7 (Homoharringtonine)
Acute myeloblasts and monocytic leukemias, and erythroleukemia
8 (Monocrotaline)
External treatment of skin cancer
9 (Lycobetaine)
Ovarian carcinoma and gastric cancer
10 (Colchicinamide)
Mammary carcinoma
11 (d-tetrandrine)
Lung cancer
12 ([-]-sophocarpine)
Trophocytic tumor, chorionepothelioma and leukemia
13 (Indirubin)
Chronic myelocytic leukemia
14 (MiV'-Dimethylindirubin)
Chronic myelocytic leukemia
15 (W-methylindirubin oxime)
Chronic myelocytic leukemia
16 (Curzerenone)
Uterine cervix and skin carcinomas
17 (Curcumol)
Early stage cervix cancer
18 (Curdione)
Early stage cervix cancer
19 (Oridonin)
Last stage of cancer of esophagus
20 (Gossypol)
Stomach, esophageal, liver, mammary, and bladder cancers
21 (Camptothecin)
Gastric, rectal, colonic, and bladder cancers
173
HUMAN MEDICINAL AGENTS FROM PLANTS
Ri 13, Indirubin: R = R3 = H, R = O 14, N,N -Dimethylindirubin: Rj R3 = C H 3 , R O x
2
f
=
=
2
17, Curcumol
12. LEE Antineoplastic Agents from Chinese Traditional Medicine
175
growing solid tumors. On the basis of this approach, many novel cytotoxic antitumor agents have been isolated and characterized from Chinese medicinal materials, and some of their representative examples are very briefly discussed below. Sesquiterpene Lactones. Several potent cytotoxic antitumor germacranolides have been isolated. These include molephantin (31) (57), molephantinin (32) (52), and phantomolin (33) (53) from Elephantopus mollis (Bei Deng Shu Wu) (Compositae) as well as eupaformonin (34) (54) and eupaformosanin (35) (55) from Eupaforium formosanum (Shan Che Lan) (Compositae). Compound 35 showed remarkable antitumor activity against the fast-growing solid tumor Walker 256 carcinosarcoma with a T/C of 471% at 2.5 mg/kg (Table I) and deserves further development as a potentially useful anticancer drug. The known pseudoguaianolide, helenalin (36), was isolated from Anaphalis morrisonicola (Yu Shan Shu Chu Tsao) (Compositae) (50, 56). An extensive study on the structure-activity relationships among 36-related sesquiterpene lactones and derivatives by this laboratory (57-59) has established that an enone 0=CCH=CH system, either present in the form of a p-unsubstituted cyclopentenone or an exocyclic a-methylene-y-lactone, as seen in 36, is regarded as an alkylating center and is directly responsible for its enhanced cytotoxic antineoplastic activity, possibly via a rapid Michael-type addition of sulfhydryl group-bearing macromolecules in key regulatory enzymes of nucleic acid and cellular metabolism. The bis-helenalinyl esters including bis-helenalinyl malonate (37), which was designed based on the fact that both an enone 0=C-CH=CH system and lipophilicity could contribute to enhanced cytotoxic antitumor activity (60), showed potent antileukemic activity (P-388-UNC) with T/C=261% at 15 mg/kg (67). Both 36 and 37 are potent inhibitors of IMP dehydrogenase (62) and of protein synthesis by preventing the formation of the 48S initiation complex specifically inactivating eIF-3 (63, 64). Diterpenes. Two antileukemic diterpenes from Daphne genkwa (Yuan Hua) (Thymelaeaceae) are the new genkwadaphnin (38) and the known yuanhuacin (39), which was previously reported as odoracin or gnidilatidin (65). Compounds 38 and 39 demonstrated potent antileukemic (P-388) activity in low doses (Table I). Compound 39 is used clinically as an abortifacient in China (66). Other novel antileukemic diterpene esters from Euphorbia kansui (Kan Sui) (Euphorbiaceae) include kansuiphorin-A (40) and -B (41) (67). Compound 40 is also selectively cytotoxic to certain human cancer cell lines, such as leukemia, nonsmall-cell lung cancer, colon cancer, melanoma, and renal cancer cells (Table II). While Kan Sui is one of the commonly prescribed anti-cancer herbs in China, further development of 40 and 41 as potentially useful antitumor agents is needed. Pseudolaric acid-A (42) and -B (43), the novel diterpene acids isolated from the root bark of Pseudolaris kaempferi (Tu Jin Pi) (Pinaceae) showed potent cytotoxicity. Compound 42 is more effective against leukemia P-388, CNS cancer U-251, and melanoma SK-MEL-5, while 43 inhibits preferentially leukemias HL60TB and P-388, colon cancer SW-620, CNS cancer TE 671, melanoma SK-MEL2, and ovarian cancer A-2780 (68). Quassinoids. The fruit of Brucea javanica (Simaroubaceae), known as Ya Tan Tzu in Chinese folklore, has been used as a herbal remedy for human cancer, amebiasis, and malaria in traditional Chinese medicine. Bioassay-directed fractionation of the antitumor-active extract of B. javanica in this laboratory led to the isolation of bruceoside-A (44) and -B (45), the first two novel quassinoid
176
HUMAN MEDICINAL AGENTS FROM PLANTS
34,
CH3CO2
Eupaformonin: R=H Eupaformosanin:
35,
R=
—CO
HOH2C
CHgOH
33, Phantomolin
37, Bis-helenalinyl Malonate
CH -(CHd -COO 3
10
20 CH200C(CH2)i4CH3
38, Genkwadaphnin: R= 39, Yuanhuacin: R= -CH=CH-CH=CH(CH2) CH 4
3
O
0
CH -(CH ) ;T~^'o 3
2 1
CH20CO(CH ) CH 2
14
3
41, Kansuiphorin-B 42, Pseudolaric Acid-A: R = CH 43, Pseudolaric Acid-B: R = COOCH 3
R
HOOC
3
Antineoplastic AgentsfromChinese Traditional Medicine
a
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177
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186
HUMAN MEDICINAL AGENTS FROM PLANTS
Polyacetylenes. A new cytotoxic polyacetylene isolated from Seseli mairei (Chu Yeh Fang Fong) (Umbelliferae) is seselidiol (93) (110). Polyphenols. Acrovestone (94), a polyphenol, was isolated from Acronychia pedunculata (Chiang Cheng Hsiang) (Rutaceae) as a cytotoxic agent (111). Styrylpyrones. Goniothalamus amuyon (Annonaceae) afforded a cytotoxic styrylpyrone, goniodiol-7-monoacetate (95) (772). Conclusion. In view of the substantial progress which has been made recently in bringing new antineoplastic agents and their analogs from Chinese traditional medicine into clinical use or clinical trials as anticancer agents as mentioned above, the future must be visualized as an optimistic one. New anticancer agents, especially anti-solid tumor agents, will be continuously discovered, based on NCI's new screening strategy. The new leads discussed above could be further developed or modified to yield useful drugs or be subjected to biochemical and pharmacological investigations to increase the understanding of tumor-cell biology. Continuing searches among Chinese medicinal plants and the semi-synthesis of their analogs will undoubtedly lead to further examples of novel plant-derived antineoplastic agents. Acknowledgments. I would like to thank my collaborators who contributed in many ways to the completion of much of this research work, and who are cited in the accompanying references. This investigation was supported by grants from the National Cancer Institute (CA 17625) and the American Cancer Society (CH 370 and DHP-13E). Literature Cited 1.
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40. van Maanen, J. M. S.; De Ruiter, C.; Kootstra, P. R.; Broersen, J.; De Vries, J.; Laffeur, M . V. M.; Retel, J.; Kriek, E.; Pinedo, H. M . Proc.Am.Assoc. Cancer Res. 1986, 27, 308. 41. Sakurai, H.; Miki, T.; Imakura, Y.; Shibuya, M . ; Lee, K. H. Molec. Pharmacol. 1991, 40, 965-973. 42. Haim, N.; Roman, J.; Nemec, J.; Sinha, B. K. Biochem. Biophys. Res. Commun. 1986, 135, 215-220 43. van Maanen, J. M . S.; De Ruiter, C.; De Vries, J.; Kootstra, P. R.; Gobars, G. Pinedo, H. M . Eur. J. Cancer Clin. Oncol. 1985, 21, 1099-1106. 44. Lee, K. H.; Beers, S. A.; Mori, M.; Wang, Z. Q.; Kuo, Y. H.; Li, L.; Liu, S. Y.; Chang, J. Y.; Han, F. S.; Cheng, Y. C. J. Med. Chem. 1990, 33, 1364-1368. 45. Wang, Z. Q.; Kuo, Y. H.; Schnur, D.; Bowen, J. P.; Liu, S. Y.; Han, F. S.; Chang, J. Y.; Cheng, Y. C.; Lee, K. H. J. Med. Chem. 1990, 33, 26602666. 46. Chang, J. Y.; Han, F. S.; Liu, S. Y.; Wang, Z. Q.; Lee, K. H.; Cheng, Y. C. Cancer Res. 1991, 51, 1755-1759. 47. Geran, R. I.; Greenberg, N. H.; MacDonald, M . M.; Schumacher, A. M . ; Abbott, J. B. Cancer Chemother. Rep., Part 3, 1972, 1-88. 48. Boyd, M. R. In Cancer: Principles and Practice of Oncology Updates; DeVita, V. Y.; Hellman, S; Rosenberg, S. A., Eds.; J. B. Lipppincott: Philadelphia, 1989, 1-12. 49. Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Gray-Goodrich, M . ; Campbell, H.; Mayo, J.; Boyd, M. J. Natl. Cancer Inst. 1991, 83, 757-766. 50. Lee, K. H., Program & Abstract - 16th Natl. Med. Chem. Symposium ACS, Kalamazoo, Michigan, June 18-22, 1978, 43-58. 51. Lee, K. H.; Furukawa, H.; Kozuka, M . ; Huang, H. C.; Luhan, P. A.; McPhail, A. T. J. Chem Soc., Chem. Commun. 1973, 476-477. 52. Lee, K. H.; Ibuka, T.; Huang, H. C.; Harris, D. L. J. Pharm. Sci. 1975, 64, 1077-1078. 53. McPhail, A. T.; Onan, K. D.; Lee, K. H.; Ibuka, T.; Kozuka, M.; Shingu, T.; Huang, H. C. Tetrahedron Lett. 1974, 32, 2739-2741. 54. McPhail, A. T.; Onan, K. D.; Lee, K. H.; Ibuka, T.; Huang, H. C. Tetrahedron Lett. 1974, 36, 3203-3206. 55. Lee, K. H.; Kimura, T.; Haruna, M.; McPhail, A. T.; Onan, K. D.; Huang, H. C. Phytochemistry. 1977, 16, 1068-1070. 56. Lee, K. H.; Haruna, M.; Huang, H. C.; Wu, B. S.; Hall, I. H. J. Pharm. Sci. 1977, 66, 1194-1195. 57. Lee, K. H.; Huang, E. S.; Piantadosi, C.; Pagano, J. S.; Geissman, T. A. Cancer Res. 1971, 31, 1649-1654. 58. Lee, K. H.; Furukawa, H.; Huang, E. S. J. Med. Chem. 1972, 15, 609611. 59. Lee, K. H.; Hall, I. H.; Mar, E. C.; Starnes, C. O.; Elgebaly, S. A.; Waddell, T. G.; Hadgraft, R. I.; Ruffner, C. G.; Weidner, I. Science 1977, 196, 552-553. 60. Lee, K. H.; Meck, R.; Piantadosi, C.; Huang, E. S. J. Med. Chem. 1973, 16, 299-301. 61. Lee, K. H.; Ibuka, T.; Sims, D.; Muraoka, O.; Kiyokawa, H.; Hall, I. H.; Kim, H. L. J. Med. Chem. 1981, 24, 924-927. 62. Page, J. D.; Chaney, S. G.; Hall, I. H.; Lee, K. H.; Holbrook, D. J. Biochim. Biophys. Acta 1987, 926, 186-194.
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