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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 17β-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.

Original publication

DOI

10.1021/jm200483x

Type

Journal article

Journal

J Med Chem

Publication Date

14/07/2011

Volume

54

Pages

4863 - 4879

Keywords

Angiogenesis Inhibitors, Animals, Antineoplastic Agents, Cell Line, Tumor, Collagen, Drug Combinations, Drug Screening Assays, Antitumor, Estradiol, Female, Humans, Laminin, Mice, Mice, Inbred C57BL, Neovascularization, Physiologic, Nitriles, Proteoglycans, Structure-Activity Relationship, Sulfonic Acids