Abstract
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 (Kis > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Kis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis 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.
Highlights
Carbonic anhydrases are a vast family of metalloenzymes (CAs, EC 4.2.1.1.) strongly involved in regulating cell homeostasis and intracellular pH by catalyzing the reversible hydration of carbonic dioxide to bicarbonate ions1
Secondary and tertiary sulfonamides have been lately reported in the literature as efficient and selective inhibitors of the cancer-related hCA IX and XII isoforms27–31, their binding mode remains a subject of investigation32
The inhibition profile of the open saccharin-based derivatives against the two tumor-related hCA IX and XII isoforms displayed some important changes compared to parent drugs
Summary
Carbonic anhydrases are a vast family of metalloenzymes (CAs, EC 4.2.1.1.) strongly involved in regulating cell homeostasis and intracellular pH by catalyzing the reversible hydration of carbonic dioxide to bicarbonate ions1. N-substituted saccharin derivatives were subjected to reductive ring opening with an excess of NaBH4 in dry methanol at room temperature for 2–8 h to give the corresponding secondary sulfonamide compounds 1–21 in discrete yields following a previously reported procedure with slight modifications35.
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