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 (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 α,γ-diketoacids 1-3 were more effective inhibitors compared to the corresponding ethyl esters 4-6. The phenyl- and α-naphthyl-containing compounds (1, 3, 4, and 6) behaved as dual hCA IX/XII inhibitors, while the β-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,γ-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,γ-Diketocarboxylic acids and their esters act as carbonic anhydrase IX and XII selective inhibitors

Dante Rotili;
2019-01-01

Abstract

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 (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 α,γ-diketoacids 1-3 were more effective inhibitors compared to the corresponding ethyl esters 4-6. The phenyl- and α-naphthyl-containing compounds (1, 3, 4, and 6) behaved as dual hCA IX/XII inhibitors, while the β-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.
2019
Nocentini, A., Lucidi, A., Perut, F., Massa, A., Tomaselli, D., Gratteri, P., et al. (2019). α,γ-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].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11590/493058
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