Design and Synthesis of Novel C14-Hydroxyl Substituted Triptolide Derivatives as Potential Selective Antitumor Agents

It has long been considered that the free β 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 α 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 C14β-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.