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  • Title: Design and synthesis of novel C14-hydroxyl substituted triptolide derivatives as potential selective antitumor agents.
    Author: Li Z, Zhou ZL, Miao ZH, Lin LP, Feng HJ, Tong LJ, Ding J, Li YC.
    Journal: J Med Chem; 2009 Aug 27; 52(16):5115-23. PubMed ID: 19637874.
    Abstract:
    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.
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