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

Eur J Med Chem. 2017 Oct 20:139:250-262. doi: 10.1016/j.ejmech.2017.07.073.

Wagdy M Eldehna ¹, Mahmoud F Abo-Ashour ², Alessio Nocentini ³, Paola Gratteri ⁴, Ibrahim H Eissa ⁵, Mohamed Fares ⁶, Omnia E Ismael ⁷, Hazem A Ghabbour ⁸, Mahmoud M Elaasser ⁹, Hatem A Abdel-Aziz ¹⁰, Claudiu T Supuran ¹¹

Affiliations

1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt. Electronic address: wagdy2000@gmail.com.
2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt.
3 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy; Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
4 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
5 Department of Pharmaceutical Chemistry, College of Pharmacy, Al-Azhar University, Cairo, 11884, Egypt.
6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt; School of Chemistry, University of Wollongong, Wollongong, 2522, New South Wales, Australia.
7 Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, Egypt.
8 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
9 The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt.
10 Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo, 12622, Egypt.
11 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 28802125 DOI: 10.1016/j.ejmech.2017.07.073

Abstract

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 K_Is 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.

Keywords

Anticancer; Apoptosis; Benzenesulfonamide; Carbonic anhydrase inhibitors; Isatin.

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