Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 22, Issue 6, Pages 1821-1831Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.01.056
Keywords
Saccharin; Selective carbonic anhydrase XII inhibitors; N-alkylation; Cyclic tertiary sulfonamides
Funding
- EU
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A series of N-alkylated saccharin derivatives were synthesized and tested for the inhibition of four different isoforms of human carbonic anhydrase (CA, EC 4. 2.1.1): the transmembrane tumor-associated CA IX and XII, and the cytosolic CA I and II. Most of the reported derivatives inhibited CA XII in the nanomolar/low micromolar range, hCA IX with K(I)s ranging between 11 and 390 nM, whereas they were inactive against both CA I (K(I)s > 50 mu M) and II (K(I)s ranging between 39.1 nM and 50 mu M). Since CA I and II are off-targets of antitumor carbonic anhydrase inhibitors (CAIs), the obtained results represent an encouraging achievement for the development of new anticancer candidates without the common side effects of non-selective CAIs. Moreover, the lack of an explicit zinc binding function on these inhibitors opens the way towards the exploration of novel mechanisms of inhibition that could explain the high selectivity of these compounds for the inhibition of the transmembrane, tumor-associated isoforms over the cytosolic ones. (C) 2014 Elsevier Ltd. All rights reserved.
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