Selective Nanomolar Inhibitors of Carbonic Anhydrases IX and XII: Coumarin Aminophosphonates as Potential Anticancer...

Tumor-associated carbonic anhydrases IX and XII are validated targets for cancer therapy. Here we report the first exploration of coumarin aminophosphonates as inhibitors of these isoforms. Using a straightforward Kabachnik-Fields approach followed by dealkylation, we synthesized 25 novel coumarin aminophosphonates (2a-p and water-soluble 3a-i) and evaluated their activity. The compounds were screened against four hCA isoforms (I, II, IX, XII) using a stopped-flow CO₂ hydration assay and displayed remarkable selectivity for IX and XII, with nanomolar K_I values (34.8-53.2 nM for IX; 15.8-37.3 nM for XII). Cellular assays of six selected derivatives revealed micromolar cytostatic effects toward seven CA IX/XII-expressing tumor cell lines while showing negligible toxicity toward normal cells. These results identify coumarin aminophosphonates as promising scaffolds for selective CA IX/XII inhibition and warrant further studies and evaluation.