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A Class of 4-Sulfamoylphenyl-ω-aminoalkyl Ethers with Effective Carbonic Anhydrase Inhibitory Action and Antiglaucoma Effects

[Image: see text] We report a series of 4-sulfamoylphenyl-ω-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The structure–activity relationship was drawn for the inhibition of four physiologically relevant isoforms: hCA I, II, IX, and XII. Many of these compounds were highly eff...

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Autores principales: Bozdag, Murat, Pinard, Melissa, Carta, Fabrizio, Masini, Emanuela, Scozzafava, Andrea, McKenna, Robert, Supuran, Claudiu T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255726/
https://www.ncbi.nlm.nih.gov/pubmed/25358036
http://dx.doi.org/10.1021/jm501497m
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author Bozdag, Murat
Pinard, Melissa
Carta, Fabrizio
Masini, Emanuela
Scozzafava, Andrea
McKenna, Robert
Supuran, Claudiu T.
author_facet Bozdag, Murat
Pinard, Melissa
Carta, Fabrizio
Masini, Emanuela
Scozzafava, Andrea
McKenna, Robert
Supuran, Claudiu T.
author_sort Bozdag, Murat
collection PubMed
description [Image: see text] We report a series of 4-sulfamoylphenyl-ω-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The structure–activity relationship was drawn for the inhibition of four physiologically relevant isoforms: hCA I, II, IX, and XII. Many of these compounds were highly effective, low nanomolar inhibitors of all CA isoforms, whereas several isoform-selective were also identified. X-ray crystal structures of two new sulfonamides bound to the physiologically dominant CA II isoform showed the tails of these derivatives bound within the hydrophobic half of the enzyme active site through van der Waals contacts with Val135, Leu198, Leu204, Trp209, Pro201, and Pro202 amino acids. One of the highly water-soluble compound (as trifluoroacetate salt) showed effective IOP lowering properties in an animal model of glaucoma. Several fluorescent sulfonamides incorporating either the fluorescein-thiourea (7a–c) or tetramethylrhodamine-thiourea (9a,b) moieties were also obtained and showed interesting CA inhibitory properties for the tumor-associated isoforms CA IX and XII.
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spelling pubmed-42557262015-10-30 A Class of 4-Sulfamoylphenyl-ω-aminoalkyl Ethers with Effective Carbonic Anhydrase Inhibitory Action and Antiglaucoma Effects Bozdag, Murat Pinard, Melissa Carta, Fabrizio Masini, Emanuela Scozzafava, Andrea McKenna, Robert Supuran, Claudiu T. J Med Chem [Image: see text] We report a series of 4-sulfamoylphenyl-ω-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The structure–activity relationship was drawn for the inhibition of four physiologically relevant isoforms: hCA I, II, IX, and XII. Many of these compounds were highly effective, low nanomolar inhibitors of all CA isoforms, whereas several isoform-selective were also identified. X-ray crystal structures of two new sulfonamides bound to the physiologically dominant CA II isoform showed the tails of these derivatives bound within the hydrophobic half of the enzyme active site through van der Waals contacts with Val135, Leu198, Leu204, Trp209, Pro201, and Pro202 amino acids. One of the highly water-soluble compound (as trifluoroacetate salt) showed effective IOP lowering properties in an animal model of glaucoma. Several fluorescent sulfonamides incorporating either the fluorescein-thiourea (7a–c) or tetramethylrhodamine-thiourea (9a,b) moieties were also obtained and showed interesting CA inhibitory properties for the tumor-associated isoforms CA IX and XII. American Chemical Society 2014-10-30 2014-11-26 /pmc/articles/PMC4255726/ /pubmed/25358036 http://dx.doi.org/10.1021/jm501497m Text en Copyright © 2014 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Bozdag, Murat
Pinard, Melissa
Carta, Fabrizio
Masini, Emanuela
Scozzafava, Andrea
McKenna, Robert
Supuran, Claudiu T.
A Class of 4-Sulfamoylphenyl-ω-aminoalkyl Ethers with Effective Carbonic Anhydrase Inhibitory Action and Antiglaucoma Effects
title A Class of 4-Sulfamoylphenyl-ω-aminoalkyl Ethers with Effective Carbonic Anhydrase Inhibitory Action and Antiglaucoma Effects
title_full A Class of 4-Sulfamoylphenyl-ω-aminoalkyl Ethers with Effective Carbonic Anhydrase Inhibitory Action and Antiglaucoma Effects
title_fullStr A Class of 4-Sulfamoylphenyl-ω-aminoalkyl Ethers with Effective Carbonic Anhydrase Inhibitory Action and Antiglaucoma Effects
title_full_unstemmed A Class of 4-Sulfamoylphenyl-ω-aminoalkyl Ethers with Effective Carbonic Anhydrase Inhibitory Action and Antiglaucoma Effects
title_short A Class of 4-Sulfamoylphenyl-ω-aminoalkyl Ethers with Effective Carbonic Anhydrase Inhibitory Action and Antiglaucoma Effects
title_sort class of 4-sulfamoylphenyl-ω-aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255726/
https://www.ncbi.nlm.nih.gov/pubmed/25358036
http://dx.doi.org/10.1021/jm501497m
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