SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report the synthesis of two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides 5a-i and 6a-j as SLC-0111 enaminone congeners. The prepared enaminones were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the enaminones reported here in variable degrees. The target tumor-associated isoform hCA IX was undeniably the most affected one (K i s: 0.21-7.1 nM), with 6- to 21-fold enhanced activity than SLC-0111 (K-I = 45 nM). All the prepared enaminones displayed interesting selectivity towards hCA IX over hCA I (SI: 32 - > 35714), hCA II (SI: 2 -1689) and hCA IV (SI: 11 - > 45454). Of particular interest, bioisosteric replacement of phenyl tail with the bulkier 2-naphthyl tail, sulfonamide 6h, achieved the higher II/IX selectivity herein reported with SI of 1689.

SLC-0111 enaminone analogs, 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides, as novel selective subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform IX / Eldehna, Wagdy M; Abo-Ashour, Mahmoud F; Berrino, Emanuela; Vullo, Daniela; Ghabbour, Hazem A; Al-Rashood, Sara T; Hassan, Ghada S; Alkahtani, Hamad M; Almehizia, Abdulrahman A; Alharbi, Amal; Abdel-Aziz, Hatem A; Supuran, Claudiu T. - In: BIOORGANIC CHEMISTRY. - ISSN 0045-2068. - ELETTRONICO. - 83:(2019), pp. 0-0. [10.1016/j.bioorg.2018.11.014]

SLC-0111 enaminone analogs, 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides, as novel selective subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform IX

Berrino, Emanuela;Vullo, Daniela;Supuran, Claudiu T
2019

Abstract

SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report the synthesis of two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides 5a-i and 6a-j as SLC-0111 enaminone congeners. The prepared enaminones were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the enaminones reported here in variable degrees. The target tumor-associated isoform hCA IX was undeniably the most affected one (K i s: 0.21-7.1 nM), with 6- to 21-fold enhanced activity than SLC-0111 (K-I = 45 nM). All the prepared enaminones displayed interesting selectivity towards hCA IX over hCA I (SI: 32 - > 35714), hCA II (SI: 2 -1689) and hCA IV (SI: 11 - > 45454). Of particular interest, bioisosteric replacement of phenyl tail with the bulkier 2-naphthyl tail, sulfonamide 6h, achieved the higher II/IX selectivity herein reported with SI of 1689.
2019
83
0
0
Eldehna, Wagdy M; Abo-Ashour, Mahmoud F; Berrino, Emanuela; Vullo, Daniela; Ghabbour, Hazem A; Al-Rashood, Sara T; Hassan, Ghada S; Alkahtani, Hamad M; Almehizia, Abdulrahman A; Alharbi, Amal; Abdel-Aziz, Hatem A; Supuran, Claudiu T
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1307866
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