Among human carbonic anhydrase (CA) inhibitors, the alpha,gamma-diketocarboxylic acids and esters are still poorly investigated. Here, we report the first compounds of this class (1-6) 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 alpha,gamma-diketoacids 1-3 were more effective inhibitors compared to the corresponding ethyl esters 4-6. The phenyl- and alpha-naphthyl-containing compounds (1, 3, 4, and 6) behaved as dual hCA IX/XII inhibitors, while the beta-naphthyl analogues (2 and 5) exhibited hCA IX-selective inhibition. In MG63 and HOS osteosarcoma (OS) cell lines, the ethyl esters 5 and 6 displayed dose-dependent reduction of viability and proliferation after 72 h treatment, with 6 being more potent than 5 likely for its dual hCA IX/XII inhibition.
α-Diketocarboxylic Acids and Their Esters Act as Carbonic Anhydrase IX and XII Selective Inhibitors / Nocentini A.; Lucidi A.; Perut F.; Massa A.; Tomaselli D.; Gratteri P.; Baldini N.; Rotili D.; Mai A.; Supuran C.T.. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - STAMPA. - 10:4(2019), pp. 661-665. [10.1021/acsmedchemlett.9b00023]
α-Diketocarboxylic Acids and Their Esters Act as Carbonic Anhydrase IX and XII Selective Inhibitors
Nocentini A.;Perut F.;TOMASELLI, DANIELA;Baldini N.;
2019
Abstract
Among human carbonic anhydrase (CA) inhibitors, the alpha,gamma-diketocarboxylic acids and esters are still poorly investigated. Here, we report the first compounds of this class (1-6) 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 alpha,gamma-diketoacids 1-3 were more effective inhibitors compared to the corresponding ethyl esters 4-6. The phenyl- and alpha-naphthyl-containing compounds (1, 3, 4, and 6) behaved as dual hCA IX/XII inhibitors, while the beta-naphthyl analogues (2 and 5) exhibited hCA IX-selective inhibition. In MG63 and HOS osteosarcoma (OS) cell lines, the ethyl esters 5 and 6 displayed dose-dependent reduction of viability and proliferation after 72 h treatment, with 6 being more potent than 5 likely for its dual hCA IX/XII inhibition.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
