Structure鈥揂ctivity Relationships of C-17-Substituted Estratriene-3-O-sulfamates as Anticancer Agents

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• 作者：Fabrice Jourdan ; Mathew P. Leese ; Wolfgang Dohle ; Eric Ferrandis ; Simon P. Newman ; Surinder Chander ; Atul Purohit ; Barry V. L. Potter
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4863-4879
• 全文大小：1218K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

The synthesis and antiproliferative activities of analogues of 2-substituted estradiol-3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent confirm that an H-bond acceptor is essential for high activity; its optimal linkage to C-17 and the local environment in which it resides are defined. In the non-sulfamoylated series 17尾-acyl substitution delivers 48b, the most potent compound identified to date. In the sulfamate series a number of permutations of linker and H-bond acceptor deliver excellent activity, with 55, 61, 65, 49a, and 49b proving especially promising. The in vivo potential of these compounds was explored in the NCI hollow fiber assay and also in a mouse Matrigel model of antiangiogenesis in which 49 and 55 show significant inhibitory activity.