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.
Nocentini A., Lucidi A., Perut F., Massa A., Tomaselli D., Gratteri P., et al. (2019). α-Diketocarboxylic Acids and Their Esters Act as Carbonic Anhydrase IX and XII Selective Inhibitors. ACS MEDICINAL CHEMISTRY LETTERS, 10(4), 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.
