title: Steroidal oxathiazine inhibitors of estrone sulfatase.
abstract: The presence of estrone sulfatase in breast tumors and the high levels of circulating estrone sulfate may contribute the major portion of estrogen synthesized locally in breast tissues through conversion of estrone sulfate to estrone by the enzyme. Using inhibitors of estrone sulfatase for the treatment of estrogen-dependent (estrogen receptor positive, ER(+)) breast cancer could be a very effective therapeutic strategy for the treatment of estrogen-dependent breast tumors in postmenopausal women. Therefore, we designed and synthesized several steroidal 2',3'-oxathiazines that inhibit estrone sulfatase and have greatly reduced estrogenic side effects. Our in vitro studies indicate that the oxathiazine compounds have inhibitory activity on estrone sulfatase in MCF-7 human breast cancer cells. These estrone sulfatase inhibitors (ESIs) also inhibit the growth of MCF-7 cells induced by estrone sulfate. In addition, our in vivo experiments demonstrate that our ESIs have moderate antitumor activity against MCF-7 breast cancer xenografts in Balb/c athymic nude mice. The synthesis and biological activity of a number of these unique steroidal ESIs are described.
authors.affiliation: SRI International, Life Science Division, 333 Ravenswood Avenue Bldg., 100-2, Menlo Park, CA 94025, USA. richard.peters@sri.com
authors.forename: Richard H
authors.initials: RH
authors.lastname: Peters
authors.forename: Wan Ru
authors.initials: WR
authors.lastname: Chao
authors.forename: Barbara
authors.initials: B
authors.lastname: Sato
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Shigeno
authors.forename: Nurulain T
authors.initials: NT
authors.lastname: Zaveri
authors.forename: Masato
authors.initials: M
authors.lastname: Tanabe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013256:Steroids / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013429:Sulfatases / Q000037:antagonists & inhibitors*; D013843:Thiazines / Q000138:chemical synthesis* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013256:Steroids; D013843:Thiazines; D004970:Estrone; D013429:Sulfatases; C020121:estrone sulfatase; C017296:estrone sulfate