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

✍ Scribed by Dr. Paul M. Wood; Dr. L. W. Lawrence Woo; Dr. Mark P. Thomas; Dr. Mary F. Mahon; Dr. Atul Purohit; Prof. Barry V. L. Potter

• Book ID: 102805517
• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 922 KB
• Volume: 6
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.201100145

✦ Synopsis

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-(1__H__-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.