Click-tailed coumarins with potent and selective inhibitory action against the tumor-associated carbonic anhydrases IX and XII

Coumarins behave as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) with a mechanism of inhibition distinct from other classes of inhibitors. A series of 7-substituted coumarins incorporating aryl-triazole moieties were prepared by click chemistry procedures starting from 7-hydroxycoumarin or 4-methyl-7-aminocoumarin. The panel of new compounds was assayed for the inhibition of the cytosolic, widespread human (h) isoforms hCA I and II, and the transmembrane, tumor-associated ones hCA IX and XII. Most of the coumarins were weak inhibitors or did not inhibit significantly hCA I and II, but showed low nanomolar inhibitory action against the transmembrane isoforms (KI of 14.3–34.4 nM against hCA IX and of 4.7–37.8 nM against hCA XII). Since many hypoxic tumors overexpress hCA IX/XII, and as these targets were recently validated for obtaining antitumor/antimetastatic agents, with one inhibitor in Phase I clinical trials, the present findings constitute an interesting extension to the knowledge of non-sulfonamide, selective inhibitors of CA isoforms involved in serious pathologies.

KI (hCA I) = 172.8 → 10000 nM; KI (hCA II) 99.6 → 10000 nM; KI (hCA IX) = 14.3–34.4 nM; KI (hCA XII) = 4.7–37.8 nM.Figure optionsDownload as PowerPoint slide