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.
J Med Chem. 2009 Aug 27;52(16):5115-23. doi: 10.1021/jm900342g.
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.
长期以来，人们一直认为雷公藤红素（1）C14 位上的游离β-羟基对于其强大的抗癌活性是必不可少的。在这项研究中，我们合成了 1 的新型衍生物，其中 1 位的羟基被环氧基（4-8）或五元环（11-13）取代。尽管化合物（4-8）的体外抗癌活性不如 1，但仍具有显著的活性。尽管（14S）-14,21-环氧雷公藤红素（4）在 C14 位具有α氧构型，但在所有这些衍生物中显示出最高的活性，这显然对化合物 1 的 C14β-羟基的必要性提出了传统观点的挑战。进一步的研究表明，化合物 4 不仅显示出广谱的体外抗癌活性，而且还表现出明显的选择性体内抗癌活性，特别是对人卵巢 SK-OV-3 和前列腺 PC-3 癌症，其毒性明显低于 1。值得注意的是，化合物 4 对多药耐药癌细胞也具有高度的疗效。因此，我们的研究为 1 的构效关系提供了新的见解，并产生了一种具有独特抗癌活性的有前途的抗癌药物候选物。
