Design and synthesis of novel C14-hydroxyl substituted triptolide derivatives as potential selective antitumor agents.
It has long been considered that the free beta hydroxyl group at C14 of triptolide (1) is essential to its potent anticancer activity. In this study, we synthesized novel derivatives of 1 with a hydroxyl group substituted by epoxy groups (4-8) or a five-membered ring (11-13). Compounds (4-8) showed significant in vitro anticancer activity although less potent than 1. Although with an alpha oxygen configuration at the C14 position, (14S)-14,21-epoxytriptolide (4) exhibited the highest potency among all these derivatives, clearly challenging the traditional viewpoint on the necessity of C14beta-hydroxyl group of compound 1. Further studies revealed that while displaying broad spectrum in vitro anticancer activity, compound 4 demonstrated prominent selective in vivo anticancer activity, particularly against human ovarian SK-OV-3 and prostate PC-3 cancers with obviously lower toxicity than 1. Noticeably, compound 4 was also highly effective against multidrug resistant cancer cells. Therefore, our study gives new insights into the structure-activity relationship of 1 and also produces a promising anticancer drug candidate with unique anticancer activities.
Li
Zheng
Z
Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.
Zhou
Zhao-Li
ZL
Miao
Ze-Hong
ZH
Lin
Li-Ping
LP
Feng
Hui-Jin
HJ
Tong
Lin-Jiang
LJ
Ding
Jian
J
Li
Yuan-Chao
YC
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010618:Phenanthrolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C550438:(14S)-14,21-epoxytriptolide; D000970:Antineoplastic Agents; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D010618:Phenanthrolines; C001899:triptolide