2-Substituted Estradiol Bis-sulfamates, Multitargeted Antitumor Agents:  Synthesis, In Vitro SAR, Protein Crystallography, and In Vivo Activity

• Published in: Journal of medicinal chemistry 2006-12, Vol.49 (26), p.7683-7696
• Main Authors: Leese, Mathew P, Leblond, Bertrand, Smith, Andrew, Newman, Simon P, Di Fiore, Anna, De Simone, Giuseppina, Supuran, Claudiu T, Purohit, Atul, Reed, Michael J, Potter, Barry V. L
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites; Biological and medical sciences; Breast Neoplasms - drug therapy; Carbonic Anhydrase II - chemistry; Carbonic Anhydrase II - metabolism; Carcinoma, Lewis Lung - blood supply; Carcinoma, Lewis Lung - drug therapy; Cell Proliferation - drug effects; Crystallography, X-Ray; Estradiol - analogs & derivatives; Estradiol - chemical synthesis; Estradiol - pharmacology; Female; General aspects; Humans; Medical sciences; Mice; Mice, Nude; Models, Molecular; Neovascularization, Pathologic - drug therapy; Pharmacology. Drug treatments; Steryl-Sulfatase - antagonists & inhibitors; Steryl-Sulfatase - metabolism; Structure-Activity Relationship; Sulfonic Acids - chemistry; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Zinc - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060705x

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.