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

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-nanom...

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Autores principales: Wood, Paul M, Woo, L W Lawrence, Thomas, Mark P, Mahon, Mary F, Purohit, Atul, Potter, Barry V L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: WILEY-VCH Verlag 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170879/
https://www.ncbi.nlm.nih.gov/pubmed/21608133
http://dx.doi.org/10.1002/cmdc.201100145
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author Wood, Paul M
Woo, L W Lawrence
Thomas, Mark P
Mahon, Mary F
Purohit, Atul
Potter, Barry V L
author_facet Wood, Paul M
Woo, L W Lawrence
Thomas, Mark P
Mahon, Mary F
Purohit, Atul
Potter, Barry V L
author_sort Wood, Paul M
collection PubMed
description 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: 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.
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spelling pubmed-31708792011-09-14 Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates Wood, Paul M Woo, L W Lawrence Thomas, Mark P Mahon, Mary F Purohit, Atul Potter, Barry V L ChemMedChem Full Paper 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: 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. WILEY-VCH Verlag 2011-08-01 2011-05-23 /pmc/articles/PMC3170879/ /pubmed/21608133 http://dx.doi.org/10.1002/cmdc.201100145 Text en Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
spellingShingle Full Paper
Wood, Paul M
Woo, L W Lawrence
Thomas, Mark P
Mahon, Mary F
Purohit, Atul
Potter, Barry V L
Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates
title Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates
title_full Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates
title_fullStr Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates
title_full_unstemmed Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates
title_short Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates
title_sort aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole and vorozole templates
topic Full Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170879/
https://www.ncbi.nlm.nih.gov/pubmed/21608133
http://dx.doi.org/10.1002/cmdc.201100145
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