Synthesis, Antitubulin, and Antiproliferative SAR of Analogues of 2-Methoxyestradiol-3,17-O,O-bis-sulfamate

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• 作者：Fabrice Jourdan ; Mathew P. Leese ; Wolfgang Dohle ; Ernest Hamel ; Eric Ferrandis ; Simon P. Newman ; Atul Purohit ; Michael J. Reed ; Barry V. L. Potter
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：April 8, 2010
• 年：2010
• 卷：53
• 期：7
• 页码：2942-2951
• 全文大小：920K
• 年卷期：v.53,no.7(April 8, 2010)
• ISSN：1520-4804

文摘

The synthesis and antiproliferative activity of analogues of estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent reveal that an H-bond acceptor is essential for high antiproliferative activity. The local environment in which this H-bond acceptor lies can be varied to an extent. The C-17-oxygen linker can be deleted or substituted with an electronically neutral methylene group, and replacement of the terminal NH₂ with a methyl group is also acceptable. Mesylates 10 and 14 prove equipotent to the E2bisMATEs 2 and 3, while sulfones 20 and 35 display enhanced in vitro antiproliferative activity. In addition, the SAR of 2-substituted estradiol-3-O-sulfamate derivatives as inhibitors of tubulin polymerization has been established for the first time. These agents inhibit the binding of radiolabeled colchicine to tubulin.