期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 24, 期 5, 页码 1256-1260出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2014.01.076
关键词
Carbonic anhydrase; Sulfocoumarin; 1,4-Substituted 1,2,3-triazole; 1,5-Substituted 1,2,3-triazole; Click chemistry; Isoform-selective inhibitor; Tumor-associated carbonic anhydrase
资金
- EU
A series of 6-substituted sulfocoumarins incorporating substituted-1,2,3-triazol-4-yl-/5-yl moieties were synthesized by employing click chemistry. The new sulfocoumarins incorporated cycloalkyl, tert-butyl and substituted aryl moieties at the triazole ring, and were investigated for the inhibition of four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, the cytosolic hCA I and II; and the transmembrane, tumor-associated hCA IX and XII. The triazole-substituted sulfocoumarins did not inhibit the ubiquitous, off-target cytosolic isoforms hCA I and II (K(I)s > 10 mu M) but showed effective inhibition against the two transmembrane CAs, with KIs ranging from 7.2 to 10.5 nM against hCA IX, and between 5.5 and 17.7 nM against hCA XII. As hCA IX and XII are validated anti-tumor targets, such prodrug, isoform-selective inhibitors as the sulfocoumarins reported here, may be useful for identifying suitable drug candidates for clinical trials. (c) 2014 Elsevier Ltd. All rights reserved.
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