title: Bicyclic derivatives of the potent dual aromatase-steroid sulfatase inhibitor 2-bromo-4-{[(4-cyanophenyl)(4h-1,2,4-triazol-4-yl)amino]methyl}phenylsulfamate: synthesis, SAR, crystal structure, and in vitro and in vivo activities.
abstract: The design and synthesis of a series of bicyclic ring containing dual aromatase-sulfatase inhibitors (DASIs) based on the aromatase inhibitor (AI) 4-[(4-bromobenzyl)(4H-1,2,4-triazol-4-yl)amino]benzonitrile are reported. Biological evaluation with JEG-3 cells revealed structure-activity relationships. The X-ray crystal structure of sulfamate 23 was determined, and selected compounds were docked into the aromatase and steroid sulfatase (STS) crystal structures. In the sulfamate-containing series, compounds containing a naphthalene ring are both the most potent AI (39, IC(50 AROM)=0.25 nM) and the best STS inhibitor (31, IC(50 STS)=26 nM). The most promising DASI is 39 (IC(50 AROM)=0.25 nM, IC(50 STS)=205 nM), and this was evaluated orally in vivo at 10 mg kg(-1), showing potent inhibition of aromatase (93 %) and STS (93 %) after 3 h. Potent aromatase and STS inhibition can thus be achieved with a DASI containing a bicyclic ring system; development of such a DASI could provide an attractive new option for the treatment of hormone-dependent breast cancer.
authors.affiliation: Department of Pharmacy and Pharmacology and Sterix Ltd. University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Wood
authors.forename: L W Lawrence
authors.initials: LW
authors.lastname: Woo
authors.forename: Jean-Robert
authors.initials: JR
authors.lastname: Labrosse
authors.forename: Mark P
authors.initials: MP
authors.lastname: Thomas
authors.forename: Mary F
authors.initials: MF
authors.lastname: Mahon
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Chander
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: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001141:Aromatase / Q000737:chemistry* / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D008968:Molecular Conformation; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D013451:Sulfonic Acids; D014230:Triazoles; C005741:sulfamic acid; D001141:Aromatase; D043266:Steryl-Sulfatase