α,γ-Diketocarboxylic Acids and Their Esters Act as Carbonic Anhydrase IX and XII Selective Inhibitors.

Among human carbonic anhydrase (CA) inhibitors, the α,γ-diketocarboxylic acids and esters are still poorly investigated. Here, we report the first compounds of this class (-) acting as potent inhibitors at low nanomolar level against the cancer-related human CA IX and XII, and 2-3 magnitude orders selective toward the cytosolic isoforms hCA I and II. At enzymatic level, the α,γ-diketoacids - were more effective inhibitors compared to the corresponding ethyl esters -. The phenyl- and α-naphthyl-containing compounds (, , , and ) behaved as dual hCA IX/XII inhibitors, while the β-naphthyl analogues ( and ) exhibited hCA IX-selective inhibition. In MG63 and HOS osteosarcoma (OS) cell lines, the ethyl esters and displayed dose-dependent reduction of viability and proliferation after 72 h treatment, with being more potent than likely for its dual hCA IX/XII inhibition.