title: A-ring-substituted estrogen-3-O-sulfamates: potent multitargeted anticancer agents.
abstract: Efficient and flexible syntheses of 2-substituted estrone, estradiol and their 3-O-sulfamate (EMATE) derivatives have been developed using directed ortho-lithiation methodology. 2-Substituted EMATEs display a similar antiproliferative activity profile to the corresponding estradiols against a range of human cancer cell lines. 2-Methoxy (3, 4), 2-methylsulfanyl (20, 21) and 2-ethyl EMATEs (32, 33) proved the most active compounds with 2-ethylestradiol-3-O-sulfamate (33), displaying a mean activity over the NCI 55 cell line panel 80-fold greater than the established anticancer agent 2-methoxyestradiol (2). 2-Ethylestradiol-3-O-sulfamate (33) was also an effective inhibitor of angiogenesis using three in vitro markers, and various 2-substituted EMATEs also proved to be inhibitors of steroid sulfatase (STS), a therapeutic target for the treatment of hormone-dependent breast cancer. The potential of this novel class of multimechanism anticancer agents was confirmed in vivo with good activity observed in the NCI hollow fiber assay and in a MDA-MB-435 xenograft mouse model.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, U.K.
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Leese
authors.forename: Hatem A M
authors.initials: HA
authors.lastname: Hejaz
authors.forename: Mary F
authors.initials: MF
authors.lastname: Mahon
authors.forename: Simon P
authors.initials: SP
authors.lastname: Newman
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: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D013451:Sulfonic Acids; D004970:Estrone; D004958:Estradiol; C005741:sulfamic acid; D043266:Steryl-Sulfatase