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.
Jourdan, F., Leese, M. P., Dohle, W., Hamel, E., Ferrandis, E., Newman, S. P., Purohit, A., Reed, M. J., & 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), 2942-2951. https://doi.org/10.1021/jm9018806