期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 20, 期 15, 页码 4511-4514出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.06.040
关键词
Carbonic anhydrase; Coumarin; Selective enzyme inhibitor; Tumor-associated isoforms IX and XII; Cytosolic isoforms I and II; Lead compound; Hydroxycoumarin
资金
- European Union
A series of coumarins incorporating hydroxy-, chloro- and/or chloromethyl-moieties in positions 3-, 4-, 6- and 7- of the heterocyclic ring were investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). These coumarins were very weak or ineffective as inhibitors of the house-keeping, offtarget isoforms CA I and II, but showed effective, submicromolar inhibition of the transmembrane, tumor-associated isoforms CA IX and XII. The nature and position of the groups substituting the coumarin ring greatly influenced CA inhibitory properties. 6-Hydroxycoumarin showed K(I)s > 100 mu M against CA I and II, of 0.198 mu M against CA IX and of 0.683 mu M against CA XII, being thus a selective, efficient inhibitor for the tumor-associated over cytosolic isoforms. These compounds are also excellent leads for designing isoform-selective enzyme inhibitors. (C) 2010 Elsevier Ltd. All rights reserved.
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