Document Detail


Carbonic anhydrase inhibitors. Inhibition of mammalian isoforms I-XIV with a series of natural product polyphenols and phenolic acids.
MedLine Citation:
PMID:  20185318     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A series of phenolic acids and phenol natural products, such as p-hydroxybenzoic acid, p-coumaric acid, caffeic acid, ferulic acid, gallic acid, syringic acid, quercetin, and ellagic acid, were investigated for their inhibitory effects against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). All mammalian isozymes of human (h) or murine (m) origin hCA I-hCA XII, mCA XIII and hCA XIV were inhibited in the low micromolar or submicromolar range by these (poly)phenols (K(I)s in the range of 0.87-7.79 microM). p-Hydroxybenzoic acid was the best inhibitor of all isozymes (K(I)s of 0.87-35.4 microM) and the different isozymes showed very variable inhibition profiles with these derivatives. Phenols like the ones investigated here possess a CA inhibition mechanism distinct of that of the sulfonamides/sulfamates used clinically or the coumarins. Unlike the sulfonamides, which bind to the catalytic zinc ion, phenols are anchored at the Zn(II)-coordinated water molecule and bind more externally within the active site cavity, making contacts with various amino acid residues. As this is the region with the highest variability between the many CA isozymes found in mammals, this class of compounds may lead to isoform-selective inhibitors targeting just one or few of the medicinally relevant CAs.
Authors:
Alessio Innocenti; S Beyza Oztürk Sarikaya; Ilhami Gülçin; Claudiu T Supuran
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-02-06
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  18     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-03-10     Completed Date:  2010-07-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  2159-64     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Elsevier Ltd. All rights reserved.
Affiliation:
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, 50019 Sesto Fiorentino (Florence), Italy.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biological Factors / chemistry,  pharmacology*
Carbonic Anhydrase Inhibitors / chemistry,  pharmacology*
Carbonic Anhydrases / chemistry,  metabolism*
Flavonoids / chemistry,  pharmacology*
Humans
Hydroxybenzoic Acids / chemistry,  pharmacology*
Isoenzymes / antagonists & inhibitors*,  chemistry,  metabolism
Mice
Molecular Structure
Phenols / chemistry,  pharmacology*
Stereoisomerism
Structure-Activity Relationship
Chemical
Reg. No./Substance:
0/Biological Factors; 0/Carbonic Anhydrase Inhibitors; 0/Flavonoids; 0/Hydroxybenzoic Acids; 0/Isoenzymes; 0/Phenols; 0/polyphenols; 29656-58-4/phenolic acid; EC 4.2.1.1/Carbonic Anhydrases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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