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Aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole and vorozole templates


Reference:

Wood, P. M., Woo, L. W. L., Thomas, M. P., Mahon, M. F., Purohit, A. and Potter, B. V. L., 2011. Aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole and vorozole templates. ChemMedChem, 6 (8), pp. 1423-1438.

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Official URL:

http://dx.doi.org/10.1002/cmdc.201100145

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-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.

Details

Item Type Articles
CreatorsWood, P. M., Woo, L. W. L., Thomas, M. P., Mahon, M. F., Purohit, A. and Potter, B. V. L.
DOI10.1002/cmdc.201100145
Uncontrolled Keywordsbreast cancer, sulfatase, aromatase, endocrine therapy, dual inhibitors
DepartmentsFaculty of Science > Pharmacy & Pharmacology
Faculty of Science > Chemistry
RefereedYes
StatusPublished
ID Code25817

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