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

Alessio Nocentini, Alessia Lucidi, Francesca Perut, Annamaria Massa, Daniela Tomaselli, Paola Gratteri, Nicola Baldini, Dante Rotili, Antonello Mai, Claudiu T Supuran

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)661-665
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 11 2019

Keywords

  • antitumor
  • carbonic anhydrase
  • carboxylic acid
  • Metalloenzyme
  • selective inhibition

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