Synthesis, antitubulin, and antiproliferative SAR of analogues of 2-Methoxyestradiol-3,17-O,O-bis-sulfamate

Reference:

Jourdan, F., Leese, M. P., Dohle, W., Hamel, E., Ferrandis, E., Newman, S. P., Purohit, A., Reed, M. J. and Potter, B. V. L., 2010. Synthesis, antitubulin, and antiproliferative SAR of analogues of 2-Methoxyestradiol-3,17-O,O-bis-sulfamate. Journal of Medicinal Chemistry, 53 (7), pp. 2942-2951.

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Official URL:

http://dx.doi.org/10.1021/jm9018806

Abstract

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.

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