期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 23, 期 13, 页码 2975-2981出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.05.013
关键词
Probenecid; Selective carbonic anhydrase IX inhibitors; Selective carbonic anhydrase XII inhibitors; Tertiary sulfonamides; Molecular modelling
资金
- EU
Novel amide derivatives of Probenecid were synthesized and discovered to act as potent and selective inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII. The proposed chemical transformation of the carboxylic acid into an amide group led to a complete loss of hCA I and II inhibition (K(i)s > 10,000 nM) and enhanced the inhibitory activity against hCA IX and XII, with respect to the parent compound (incorporating a COOH function). These promising biological results have been corroborated by molecular modelling studies within the active sites of the four studied human carbonic anhydrases, which enabled us to rationalize both the isoform selectivity and high activity against the tumor-associated isoforms hCA IX/XII. (C) 2015 Elsevier Ltd. All rights reserved.
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