Design, synthesis and structure-activity relationships studies on the D ring of the natural product triptolide

ChemMedChem
Hongtao XuYuan-chao Li

Abstract

Triptolide is a diterpene triepoxide natural product isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal herb. Triptolide has previously been shown to possess antitumor, anti-inflammatory, immunosuppressive, and antifertility activities. Earlier reports suggested that the five-membered unsaturated lactone ring (D ring) is essential for potent cytotoxicity, however, to the best of our knowledge, systematic structure-activity relationship studies have not yet been reported. Here, four types of D ring-modified triptolide analogues were designed, synthesized and evaluated against human ovarian (SKOV-3) and prostate (PC-3) carcinoma cell lines. The results suggest that the D ring is essential to potency, however it can be modified, for example to C18 hydrogen bond acceptor and/or donor furan ring analogues, without complete loss of cytotoxic activity. Interestingly, evaluation of the key series of C19 analogues showed that this site is exquisitely sensitive to polarity. Together, these results will guide further optimization of this natural product lead compound for the development of potent and potentially clinically useful triptolide analogues.

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Citations

Dec 4, 2014·Bioorganic & Medicinal Chemistry Letters·Hongtao XuYuanchao Li
Jun 17, 2014·Journal of Ethnopharmacology·Xiao-Jiaoyang LiLu-yong Zhang
Apr 30, 2016·Chemical Reviews·Ashwini A Ghogare, Alexander Greer
Sep 11, 2019·Beilstein Journal of Organic Chemistry·Xiang ZhangHongtao Xu
Jun 24, 2020·Chemical Biology & Drug Design·He Zhang, Gongxi Lu
Jul 30, 2019·Frontiers in Pharmacology·Weixiao AnShousong Cao
Jan 4, 2019·European Journal of Medicinal Chemistry·Hongtao Xu, Bo Liu
Oct 25, 2020·European Journal of Medicinal Chemistry·Jun LiuHongxiang Lou

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