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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. Estradiol 3,17-O,O-bis-sulfamates 20 and 21, in contrast to the 17-O-monosulfamate 11, proved to be excellent STS inhibitors. 2-Substituted E2bisMATEs 21 and 23 additionally exhibited potent antiproliferative activity with mean graph midpoint values of 18-87 nM in the NCI 60-cell-line panel. 21 Exhibited antiangiogenic in vitro and in vivo activity in an early-stage Lewis lung model, and 23 dosed p.o. caused marked growth inhibition in a nude mouse xenograft tumor model. Modeling studies suggest that the E2bisMATEs and 2-MeOE2 share a common mode of binding to tubulin, though COMPARE analysis of activity profiles was negative. 21 was cocrystallized with carbonic anhydrase II, and X-ray crystallography revealed unexpected coordination of the 17-O-sulfamate of 21 to the active site zinc and a probable additional lower affinity binding site. 2-Substituted E2bisMATEs are attractive candidates for further development as multitargeted anticancer agents.

Original publication




Journal article


J Med Chem

Publication Date





7683 - 7696


Animals, Antineoplastic Agents, Binding Sites, Breast Neoplasms, Carbonic Anhydrase II, Carcinoma, Lewis Lung, Cell Proliferation, Crystallography, X-Ray, Estradiol, Female, Humans, Mice, Mice, Nude, Models, Molecular, Neovascularization, Pathologic, Steryl-Sulfatase, Structure-Activity Relationship, Sulfonic Acids, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Zinc