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

Graphical abstract Two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides (5a–i and 6a–j) were synthesized as SLC-0111 enaminone congeners. 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). Highlights • Two series of enaminones 5a–i and 6a–j were designed and synthesized as SLC-0111 congeners. • Inhibitory activities of such enaminones were evaluated toward hCA I, II, IV and IX isoforms. • They emerged as subnanomolar hCA IX inhibitors (K I s: 0.21–0.31 nM), except 5b , 5c and 5g. • They displayed 6- to 21-fold enhanced hCA IX inhibitory activity than SLC-0111. • All enaminones displayed interesting selectivity towards hCA IX over hCA II (SI: 2 – 1689). 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 CO 2 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. [ABSTRACT FROM AUTHOR]