designed synthesized

carbonic anhydrase

European Journal of Medicinal Chemistry

As a front-runner selective CA IX inhibitor currently in Phase Ib/II clinical trials , SLC-0111 has been herein exploited as a lead molecule for development of new different sets of N -phenyl-2-(phenylsulfonyl)acetamides/propanamides incorporating different functionalities; primary sulfonamide ( 5a-f ), free carboxylic ( 8a , 8d ), ethyl ester ( 8b , 8e ), acetyl ( 8c , 8f ) and nitro ( 10a , 10b ), as potential carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. All the prepared analogues have been examined for their CA inhibitory activities towards four human ( h ) isoenzymes , h CA I, II, IX and XII. Interestingly, replacement of SLC-0111 ureido linker with the flexible sulfonyl acetamide linker, as well as linker branching and elongation strategies successfully enhanced the inhibitory action toward h CA IX isoform, such as in sulfones 5a-d and 5f which displayed better activity than SLC-0111. Furthermore, sulfonamide-based sulfone ( 5f ) and carboxylic acid-based sulfones ( 8a and 8d ) demonstrated interesting selectivity toward the tumor-related h CA IX isoform over both h CA I and h CA II, which suggests them as promising candidates for further development as potential anticancer candidates. Thereafter, the anti-proliferative action for sulfones 5f , 8a and 8d was examined against breast (MCF-7) and colon (HCT-116) cancer cell lines. Also, sulfone 5f was further assessed for its impact on the cell cycle progression and apoptosis in HCT-116 cells.

Identification of N-phenyl-2-(phenylsulfonyl)acetamides/propanamides as new SLC-0111 analogues: Synthesis and evaluation of the carbonic anhydrase inhibitory activities