- Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates
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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=0.87nM; STS: IC50=593nM). 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=0.52nM; STS: IC50=280nM). The docking of each enantiomer and other ligands into the aromatase and sulfatase active sites was also investigated.
- Wood, Paul M.,Woo, L.W. Lawrence,Thomas, Mark P.,Mahon, Mary F.,Purohit, Atul,Potter, Barry V.L.
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p. 1423 - 1438
(2012/06/30)
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