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.
α,γ-Diketocarboxylic acids and their esters act as carbonic anhydrase IX and XII selective inhibitors / Nocentini, Alessio; Lucidi, Alessia; Perut, Francesca; Massa, Annamaria; Tomaselli, Daniela; Gratteri, Paola; Baldini, Nicola; Rotili, Dante; Mai, Antonello; Supuran, Claudiu T.. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 10:4(2019), pp. 661-665. [10.1021/acsmedchemlett.9b00023]
α,γ-Diketocarboxylic acids and their esters act as carbonic anhydrase IX and XII selective inhibitors
Alessia Lucidi;Daniela Tomaselli;Dante Rotili
;Antonello Mai
;Claudiu T. Supuran
2019
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.File | Dimensione | Formato | |
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