Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates

作者：Wood Paul M^*; Woo L W Lawrence; Thomas Mark P; Mahon Mary F; Purohit Atul; Potter Barry V L

来源：ChemMedChem, 2011, 6(8): 1423-1438.

DOI：10.1002/cmdc.201100145

• aromatase
• breast cancer
• dual inhibitors
• endocrine therapy
• sulfatase

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-cyanophen-yl)-2-(1H-1,2,4-triazol-1-yl)ethyl)phenyl sulfamate is the most potent DASI (aromatase: IC(50) = 0.87 nM; STS: IC(50) = 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: IC(50) = 0.52 nM; STS: IC(50) = 280 nM). The docking of each enantiomer and other ligands into the aromatase and sulfatase active sites was also investigated.

• 出版日期2011-8-1