TY - JOUR
T1 - New selective carbonic anhydrase IX inhibitors
T2 - Synthesis and pharmacological evaluation of diarylpyrazole-benzenesulfonamides
AU - Rogez-Florent, Tiphaine
AU - Meignan, Samuel
AU - Foulon, Catherine
AU - Six, Perrine
AU - Gros, Abigaëlle
AU - Bal-Mahieu, Christine
AU - Supuran, Claudiu T.
AU - Scozzafava, Andrea
AU - Frédérick, Raphaël
AU - Masereel, Bernard
AU - Depreux, Patrick
AU - Lansiaux, Amélie
AU - Goossens, Jean François
AU - Gluszok, Sébastien
AU - Goossens, Laurence
PY - 2013/3/15
Y1 - 2013/3/15
N2 - 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.
AB - 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.
KW - Aryl sulfonamide inhibitors
KW - Breast cancer
KW - Carbonic anhydrase
KW - Doxorubicin
KW - Hypoxia
KW - Pyrazole
UR - http://www.scopus.com/inward/record.url?scp=84874529763&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2012.10.029
DO - 10.1016/j.bmc.2012.10.029
M3 - Article
C2 - 23168081
AN - SCOPUS:84874529763
SN - 0968-0896
VL - 21
SP - 1451
EP - 1464
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 6
ER -