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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 NH(2) 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.

Original publication

DOI

10.1021/jm9018806

Type

Journal article

Journal

J Med Chem

Publication Date

08/04/2010

Volume

53

Pages

2942 - 2951

Keywords

Animals, Antineoplastic Agents, Cattle, Cell Line, Tumor, Cell Proliferation, Colchicine, Estradiol, Humans, Inhibitory Concentration 50, Protein Multimerization, Protein Structure, Quaternary, Structure-Activity Relationship, Tubulin