2-Substituted Estradiol Bis-sulfamates, Multitargeted Antitumor Agents: Synthesis, In Vitro SAR, Protein Crystallography, and In Vivo Activity

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• 作者：Mathew P. Leese ; Bertrand Leblond ; Andrew Smith ; Simon P. Newman ; Anna Di Fiore ; Giuseppina De Simone ; Claudiu T. Supuran ; Atul Purohit ; Michael J. Reed ; Barry V. L. Potter
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：December 28, 2006
• 年：2006
• 卷：49
• 期：26
• 页码：7683 - 7696
• 全文大小：410K
• 年卷期：v.49,no.26(December 28, 2006)
• ISSN：1520-4804

文摘

The anticancer activities and SARs of estradiol-17-O-sulfamates and estradiol 3,17-O,O-bis-sulfamates(E2bisMATEs) as steroid sulfatase (STS) inhibitors and antiproliferative agents are discussed. Estradiol3,17-O,O-bis-sulfamates 20 and 21, in contrast to the 17-O-monosulfamate 11, proved to be excellent STSinhibitors. 2-Substituted E2bisMATEs 21 and 23 additionally exhibited potent antiproliferative activity withmean graph midpoint values of 18-87 nM in the NCI 60-cell-line panel. 21 Exhibited antiangiogenic invitro and in vivo activity in an early-stage Lewis lung model, and 23 dosed p.o. caused marked growthinhibition in a nude mouse xenograft tumor model. Modeling studies suggest that the E2bisMATEs and2-MeOE2 share a common mode of binding to tubulin, though COMPARE analysis of activity profiles wasnegative. 21 was cocrystallized with carbonic anhydrase II, and X-ray crystallography revealed unexpectedcoordination of the 17-O-sulfamate of 21 to the active site zinc and a probable additional lower affinitybinding site. 2-Substituted E2bisMATEs are attractive candidates for further development as multitargetedanticancer agents.