title: Structure-activity relationships of C-17 cyano-substituted estratrienes as anticancer agents.
abstract: The synthesis, SAR, and preclinical evaluation of 17-cyanated 2-substituted estra-1,3,5(10)-trienes as anticancer agents are discussed. 2-Methoxy-17beta-cyanomethylestra-1,3,5(10)-trien-3-ol ( 14), but not the related 2-ethyl derivative 7, and the related 3- O-sulfamates 8 and 15 display potent antiproliferative effects (MCF-7 GI 50 300, 60 and 70 nM, respectively) against human cancer cells in vitro. Investigation of the SAR reveals that a sterically unhindered hydrogen bond acceptor attached to C-17 is most likely key to the enhanced activity. Compound 8 displayed significant in vitro antiangiogenic activity, and its ability to act as a microtubule disruptor was confirmed. Inhibitory activity of the sulfamate derivatives against steroid sulfatase and carbonic anhydrase II (hCAII) was also observed, and the interaction between 15 and hCAII was investigated by protein crystallography. The potential of these multimechanism anticancer agents was confirmed in vivo, with promising activity observed for both 14 and 15 in an athymic nude mouse MDA-MB-231 human breast cancer xenograft model.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Leese
authors.forename: Fabrice L
authors.initials: FL
authors.lastname: Jourdan
authors.forename: Keira
authors.initials: K
authors.lastname: Gaukroger
authors.forename: Mary F
authors.initials: MF
authors.lastname: Mahon
authors.forename: Simon P
authors.initials: SP
authors.lastname: Newman
authors.forename: Paul A
authors.initials: PA
authors.lastname: Foster
authors.forename: Chloe
authors.initials: C
authors.lastname: Stengel
authors.forename: Sandra
authors.initials: S
authors.lastname: Regis-Lydi
authors.forename: Eric
authors.initials: E
authors.lastname: Ferrandis
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: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024402:Carbonic Anhydrase II / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004963:Estrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C529292:2-methoxy-17-cyanomethylestra-1,3,5(10)-trien-3-ol; C526437:2-methoxy-3-O-sulfamoyl-17-cyanomethylestra-1,3,5(10)-triene; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D004963:Estrenes; D009570:Nitriles; D050257:Tubulin Modulators; D004958:Estradiol; D043266:Steryl-Sulfatase; D024402:Carbonic Anhydrase II