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

• DOI: 10.1016/j.ejmech.2017.07.073
• Publication Date: 2017-08-01T03:19:00Z
• Authors: Wagdy M. Eldehna; Mahmoud F. Abo-As...; Alessio Nocentini; Paola Gratteri; Ibrahim H. Eissa; Mohamed Fares; Omnia E. Ismael; Hazem A. Ghabbour; Mahmoud M. Elaasser; Hatem A. Abdel-Aziz; Claudiu T. Supuran
• Keywords: Models, Molecular; 0301 basic medicine; Sulfonamides; Indoles; Dose-Response Relationship, Drug; Molecular Structure; Antineoplastic Agents; Social and Behavioral Sciences; 3. Good health; Structure-Activity Relationship; 03 medical and health sciences; Medicine and Health Sciences; MCF-7 Cells; Humans; Caco-2 Cells; Drug Screening Assays, Antitumor; Anticancer; Apoptosis; Benzenesulfonamide; Carbonic anhydrase inhibitors; Isatin; Antineoplastic Agents; Caco-2 Cells; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Indoles; MCF-7 Cells; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Sulfonamides; Pharmacology; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Cell Proliferation

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 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. In particular, hCA isoforms II and IX (tumor-associated) were more susceptible to inhibition by the synthesized derivatives, with KIs 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 (IC50 = 3.96 ± 0.21 μM), while 4j was the most active member against Caco-2 cells (IC50 = 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.