Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 21, Pages 6955-6966Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.09.041
Keywords
Carbonic anhydrase; Tumor-associated isoforms; Coumarin; Click chemistry
Funding
- Marie Curie ITN FP7 project (Dynano)
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Coumarins behave as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) with a mechanism of inhibition distinct from other classes of inhibitors. A series of 7-substituted coumarins incorporating aryl-triazole moieties were prepared by click chemistry procedures starting from 7-hydroxycoumarin or 4-methyl-7-aminocoumarin. The panel of new compounds was assayed for the inhibition of the cytosolic, widespread human (h) isoforms hCA I and II, and the transmembrane, tumor-associated ones hCA IX and XII. Most of the coumarins were weak inhibitors or did not inhibit significantly hCA I and II, but showed low nanomolar inhibitory action against the transmembrane isoforms (K-I of 14.3-34.4 nM against hCA IX and of 4.7-37.8 nM against hCA XII). Since many hypoxic tumors over-express hCA IX/XII, and as these targets were recently validated for obtaining antitumor/antimetastatic agents, with one inhibitor in Phase I clinical trials, the present findings constitute an interesting extension to the knowledge of non-sulfonamide, selective inhibitors of CA isoforms involved in serious pathologies. (C) 2015 Elsevier Ltd. All rights reserved.
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