title: Design, synthesis and structure-activity relationships studies on the D ring of the natural product triptolide.
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.
authors: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road , Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203 (China).
authors: Hongtao
authors: H
authors: Xu
authors: Huanyu
authors: H
authors: Tang
authors: Huijin
authors: H
authors: Feng
authors: Yuanchao
authors: Y
authors: Li
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010053:Ovary / Q000187:drug effects; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D029757:Tripterygium / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; C001899:triptolide
keywords: antitumor agents; cytotoxicity; natural products; structure-activity relationships; triptolide