Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 32, Issue 1, Pages 51-59Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2016.1235040
Keywords
Cancer-related isoforms; saccharin; secondary sulphonamides; selective carbonic anhydrase inhibitors
Funding
- FP7 EU projects
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A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (K(i)s> 10 mu M). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with K(i)s ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (K(i)s ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.
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