Design and synthesis of novel C14-hydroxyl substituted triptolide derivatives as potential selective antitumor agents.

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.

• Authors: Zheng Li, Zhao-Li Zhou, Ze-Hong Miao, Li-Ping Lin, Hui-Jin Feng, Lin-Jiang Tong, Jian Ding, Yuan-Chao Li
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 16 Pg. 5115-23 (Aug 27 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19637874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (14S)-14,21-epoxytriptolide
• Antineoplastic Agents
• Diterpenes
• Epoxy Compounds
• Phenanthrenes
• Phenanthrolines
• triptolide

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Crystallography, X-Ray
• Diterpenes (chemical synthesis, chemistry, pharmacology)
• Drug Design
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Epoxy Compounds (chemical synthesis, chemistry, pharmacology)
• Humans
• Mice
• Mice, Nude
• Phenanthrenes (chemical synthesis, chemistry, pharmacology)
• Phenanthrolines (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship