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Design and synthesis of novel C14-hydroxyl substituted triptolide derivatives as potential selective antitumor agents.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2009 Aug 27; Vol. 52 (16), pp. 5115-23. - Publication Year :
- 2009
-
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.
- Subjects :
- Animals
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Cell Line, Tumor
Crystallography, X-Ray
Diterpenes chemistry
Diterpenes pharmacology
Drug Design
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Epoxy Compounds chemistry
Epoxy Compounds pharmacology
Humans
Mice
Mice, Nude
Phenanthrenes chemical synthesis
Phenanthrenes chemistry
Phenanthrenes pharmacology
Phenanthrolines chemistry
Phenanthrolines pharmacology
Stereoisomerism
Structure-Activity Relationship
Antineoplastic Agents chemical synthesis
Diterpenes chemical synthesis
Epoxy Compounds chemical synthesis
Phenanthrolines chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 52
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19637874
- Full Text :
- https://doi.org/10.1021/jm900342g