title: Aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole and vorozole templates.
abstract: Concurrent inhibition of aromatase and steroid sulfatase (STS) may provide a more effective treatment for hormone-dependent breast cancer than monotherapy against individual enzymes, and several dual aromatase-sulfatase inhibitors (DASIs) have been reported. Three aromatase inhibitors with sub-nanomolar potency, better than the benchmark agent letrozole, were designed. To further explore the DASI concept, a new series of letrozole-derived sulfamates and a vorozole-based sulfamate were designed and biologically evaluated in JEG-3 cells to reveal structure-activity relationships. Amongst achiral and racemic compounds, 2-bromo-4-(2-(4-cyanophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl)phenyl sulfamate is the most potent DASI (aromatase: IC₅₀ =0.87 nM; STS: IC₅₀ =593 nM). The enantiomers of the phenolic precursor to this compound were separated by chiral HPLC and their absolute configuration determined by X-ray crystallography. Following conversion to their corresponding sulfamates, the S-(+)-enantiomer was found to inhibit aromatase and sulfatase most potently (aromatase: IC₅₀ =0.52 nM; STS: IC₅₀ =280 nM). The docking of each enantiomer and other ligands into the aromatase and sulfatase active sites was also investigated.
authors: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA27AY, UK.
authors: Paul M
authors: PM
authors: Wood
authors: L W Lawrence
authors: LW
authors: Woo
authors: Mark P
authors: MP
authors: Thomas
authors: Mary F
authors: MF
authors: Mahon
authors: Atul
authors: A
authors: Purohit
authors: Barry V L
authors: BV
authors: Potter
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