title: 2-substituted estradiol bis-sulfamates, multitargeted antitumor agents: synthesis, in vitro SAR, protein crystallography, and in vivo activity.
abstract: 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.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology & Sterix Ltd., University of Bath, Bath BA2 7AY, United Kingdom.
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Leese
authors.forename: Bertrand
authors.initials: B
authors.lastname: Leblond
authors.forename: Andrew
authors.initials: A
authors.lastname: Smith
authors.forename: Simon P
authors.initials: SP
authors.lastname: Newman
authors.forename: Anna
authors.initials: A
authors.lastname: Di Fiore
authors.forename: Giuseppina
authors.initials: G
authors.lastname: De Simone
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy; D024402:Carbonic Anhydrase II / Q000737:chemistry / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D015032:Zinc / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D013451:Sulfonic Acids; D004958:Estradiol; C005741:sulfamic acid; D043266:Steryl-Sulfatase; D024402:Carbonic Anhydrase II; D015032:Zinc