title: New selective carbonic anhydrase IX inhibitors: synthesis and pharmacological evaluation of diarylpyrazole-benzenesulfonamides.
abstract: 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 IC50 value, is restored at 20% level with 1μM CA IX inhibitor.
authors.affiliation: Univ. Lille Nord de France, F-59000 Lille, France.
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Rogez-Florent
authors.forename: Samuel
authors.initials: S
authors.lastname: Meignan
authors.forename: Catherine
authors.initials: C
authors.lastname: Foulon
authors.forename: Perrine
authors.initials: P
authors.lastname: Six
authors.forename: Abigaëlle
authors.initials: A
authors.lastname: Gros
authors.forename: Christine
authors.initials: C
authors.lastname: Bal-Mahieu
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Raphaël
authors.initials: R
authors.lastname: Frédérick
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Patrick
authors.initials: P
authors.lastname: Depreux
authors.forename: Amélie
authors.initials: A
authors.lastname: Lansiaux
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Goossens
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gluszok
authors.forename: Laurence
authors.initials: L
authors.lastname: Goossens
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D000096926:Benzenesulfonamides
chemical_list: D000951:Antigens, Neoplasm; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D011720:Pyrazoles; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C031280:pyrazole; C089226:CA9 protein, human