Anticancer effects of new dibenzenesulfonamides by inducing apoptosis and autophagy pathways and their carbonic anhydrase inhibitory effects on hCA I,hCA II,hCA IX,hCA XII isoenzymes |
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| Institution: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey;2. Department of Biochemistry, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey;3. Department of Physiology, Faculty of Medicine, Ataturk University, Erzurum, Turkey;4. Neurofarba Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via U. Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey;2. Division of Biochemistry, Meikai University School of Dentistry, Sakado, Saitama, Japan;3. Meikai University Research Institute of Odontology (M-RIO), Meikai University School of Dentistry, Sakado, Saitama, Japan;4. Faculty of Science, Department of Chemistry, Ataturk University, Erzurum, Turkey;5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey;6. Neurofarba Department, Sezione di Scienza Farmaceutiche e Nutraceutiche, Universita egli Studi di Firenze, Via U. Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Selcuk University, Konya, Turkey;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey;3. Department of Chemistry, Faculty of Science, Atatürk University, Erzurum, Turkey;4. Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Universita degli Studi di Firenze, Florence, Italy;1. University of Florence, Department of Chemistry “Ugo Schiff”, Via della Lastruccia 3-13, I-50019 Sesto Fiorentino, Italy;2. University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 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;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. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt;6. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;7. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;8. Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, P.O. Box 12622, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;2. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy;3. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;4. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt;5. Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, Egypt;6. Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box, 11562, Egypt;3. Neurofarba Department, Sezione di Scienze Farmaceutiche, Università degli di Studi di Firenze, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;4. The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt;5. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;6. Department of Applied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt |
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| Abstract: | In this study, new dibenzensulfonamides, 7–9, having the chemical structure 4,4′-(5′-chloro-3′-methyl-5-aryl-3,4-dihydro-1′H,H-3,4′-bipyrazole]-1′,2-diyl)dibenzenesulfonamide were synthesized in five steps to develop new anticancer drug candidates. Their chemical structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Cytotoxicities of the dibenzensulfonamides were investigated towards HCC1937, MCF7, HeLa, A549 as tumor cell lines and towards MRC5 and Vero as non-tumor cells. Carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory effects of the dibenzensulfonamides 7–9 were also evaluated on the cytosolic human (h) hCA I and II and the tumor-associated hCA IX and XII isoenzymes. Results indicate that both 7 and 8 induced cleavage of poly (ADP ribose) polymerase (PARP), activation of caspases -3, -7 and -9 which are the hallmarks of apoptosis. Meanwhile both compounds induced autophagy in HCC1937 cells which is shown by enhanced expression of LC3 and decreased level of p62 protein. The compounds tested were also effectively inhibited tumor-associated hCA IX and hCA XII isoenzymes in the range of 20.7–28.1 nM and 4.5–9.3 nM, respectively. |
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| Keywords: | Sulfonamide Pyrazole Carbonic anhydrase Anticancer Apoptosis Autophagy |
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