title: 3,17-disubstituted 2-alkylestra-1,3,5(10)-trien-3-ol derivatives: synthesis, in vitro and in vivo anticancer activity.
abstract: Estradiol-3,17-O,O-bis-sulfamates inhibit steroid sulfatase (STS), carbonic anhydrase (CA), and, when substituted at C-2, cancer cell proliferation and angiogenesis. C-2 Substitution and 17-sulfamate replacement of the estradiol-3,17-O,O-bis-sulfamates were explored with efficient and practical syntheses developed. Evaluation against human cancer cell lines revealed the 2-methyl derivative 27 (DU145 GI(50) = 0.38 microM) as the most active novel bis-sulfamate, while 2-ethyl-17-carbamate derivative 52 (GI(50) = 0.22 microM) proved most active of its series (cf. 2-ethylestradiol-3,17-O,O-bis-sulfamate 4 GI(50) = 0.21 microM). Larger C-2 substituents were deleterious to activity. 2-Methoxy-17-carbamate 50 was studied by X-ray crystallography and was surprisingly 13-fold weaker as an STS inhibitor compared to parent bis-sulfamate 3. The potential of 4 as an orally dosed anti-tumor agent is confirmed using breast and prostate cancer xenografts. In the MDA-MB-231 model, dramatic reduction in tumor growth or regression was observed, with effects sustained after cessation of treatment. 3-O-Sulfamoylated 2-alkylestradiol-17-O-carbamates and sulfamates have considerable potential as anticancer agents.
authors: Medicinal Chemistry, Department of Pharmacy and Pharmacology & Sterix Ltd., University of Bath, Bath BA2 7AY, UK.
authors: Christian
authors: C
authors: Bubert
authors: Mathew P
authors: MP
authors: Leese
authors: Mary F
authors: MF
authors: Mahon
authors: Eric
authors: E
authors: Ferrandis
authors: Sandra
authors: S
authors: Regis-Lydi
authors: Philip G
authors: PG
authors: Kasprzyk
authors: Simon P
authors: SP
authors: Newman
authors: Yaik T
authors: YT
authors: Ho
authors: Atul
authors: A
authors: Purohit
authors: Michael J
authors: MJ
authors: Reed
authors: Barry V L
authors: BV
authors: Potter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D013451:Sulfonic Acids; D004958:Estradiol