Novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino) benzenesulfonamides: Synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular modelling studies.

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European journal of medicinal chemistry, ISSN: 1768-3254, Vol: 139, Page: 250-262

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Eldehna, Wagdy M; Abo-Ashour, Mahmoud F; Nocentini, Alessio; Gratteri, Paola; Eissa, Ibrahim H; Fares, Mohamed; Ismael, Omnia E; Ghabbour, Hazem A; Elaasser, Mahmoud M; Abdel-Aziz, Hatem A; Supuran, Claudiu T Show More Hide
Elsevier BV
Pharmacology, Toxicology and Pharmaceutics; Chemistry; Medicine and Health Sciences; Social and Behavioral Sciences
article description
Herein we report the synthesis of two series of novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino)benzenesulfonamides (4a-m and 7a-g). All the newly prepared sulfonamides were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC isoforms hCA I, II, IV and IX, using a stopped-flow CO hydrase assay. In particular, hCA isoforms II and IX (tumor-associated) were more susceptible to inhibition by the synthesized derivatives, with Ks in the range of 2.6-598.2 nM for hCA II, and of 16.1-321 nM for hCA IX. All compounds (4a-m and 7a-g) were evaluated for their anti-proliferative activity against breast cancer MCF-7 and colorectal cancer Caco-2 cell lines. Compound 4c was found to be the most potent derivative against MCF-7 (IC = 3.96 ± 0.21 μM), while 4j was the most active member against Caco-2 cells (IC = 5.87 ± 0.37 μM). Compound 4c induced the intrinsic apoptotic mitochondrial pathway in MCF-7 cells; evidenced by the enhanced expression of the pro-apoptotic protein Bax and the reduced expression of the anti-apoptotic protein Bcl-2, and the up-regulated active caspase-9 and caspase-3 levels.