New selective carbonic anhydrase IX inhibitors: Synthesis and pharmacological evaluation of diarylpyrazole-benzenesulfonamides

Tiphaine Rogez-Florent, Samuel Meignan, Catherine Foulon, Perrine Six, Abigaëlle Gros, Christine Bal-Mahieu, Claudiu T. Supuran, Andrea Scozzafava, Raphaël Frédérick, Bernard Masereel, Patrick Depreux, Amélie Lansiaux, Jean François Goossens, Sébastien Gluszok, Laurence Goossens

Résultats de recherche: Contribution à un journal/une revueArticleRevue par des pairs


Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. We report the synthesis and the pharmacological evaluation of a new class of human carbonic anhydrase (hCA) inhibitors, 4-(5-aryl-2-hydroxymethyl-pyrazol-1-yl)-benzenesulfonamides. A molecular modeling study was conducted in order to simulate the binding mode of this new family of enzyme inhibitors within the active site of hCA IX. Pharmacological studies revealed high hCA IX inhibitory potency in the parameters nanomolar range. This study showed that the position of sulfonamide group in meta of the 1-phenylpyrazole increase a selectivity hCA IX versus hCA II of our compounds. An in vitro antiproliferative screening has been performed on the breast cancer MDA-MB-231 cell using doxorubicin as cytotoxic agent and in presence of selected CA IX inhibitor. The results shown that the cytotoxic efficiency of doxorubicin in an hypoxic environment, expressed in IC 50 value, is restored at 20% level with 1 μM CA IX inhibitor.

langue originaleAnglais
Pages (de - à)1451-1464
Nombre de pages14
journalBioorganic and Medicinal Chemistry
Numéro de publication6
Les DOIs
Etat de la publicationPublié - 15 mars 2013

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