A novel library of saccharin and acesulfame derivatives as potent and selective inhibitors of carbonic anhydrase IX and XII isoforms |
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| Affiliation: | 1. Department of Pharmacy, ‘G. D’Annunzio’ University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy;2. Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy;3. Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy;4. Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, Vatan Caddesi, 34093 Fatih, Istanbul, Turkey;5. Institute of Chemical Methodologies, Magnetic Resonance Laboratory ‘Annalaura Segre’, National Research Council, Via Salaria km 29.300, 00015 Monterotondo (Rome), Italy;6. Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Via U. Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;1. Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy;2. Department of Pharmacy, “G. D''Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy;3. Dipartimento di Sanità Pubblica e Malattie Infettive, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy;4. Dipartimento di Medicina Sperimentale, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy;5. Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, Vatan Caddesi, 34093 Fatih, Istanbul, Turkey;1. Department of Chemistry, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy;2. CNR, Istituto di Metodologie Chimiche, Sezione Meccanismi di Reazione, Dipartimento di Progettazione Molecolare, P.le A. Moro 5, 00185, Roma, Italy;3. Department of Physics, Unità INSTM and CISDiC University Roma Tre, Via della Vasca Navale 85, 00146, Rome, Italy;1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;2. Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt;3. Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt;4. University of Florence, Neurofarba Department, Sezione di Scienze farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;1. Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA;2. Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia;3. Polo Scientifico, Neurofarba Department and Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy;1. Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA;2. University of Florence, NEUROFARBA Department, Sezione di Farmaceutica e Nutraceutica, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;1. Università degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy;2. Chemistry Department, Kulliyyah of Science, International Islamic University, Kuantan, Malaysia;3. Pharmaceutical Chemistry Dept., College of Pharmacy, Prince Sattam Bin Abdulaziz University, Saudi Arabia;4. Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy |
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| Abstract: | Small libraries of N-substituted saccharin and N-/O-substituted acesulfame derivatives were synthesized and tested as atypical and selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). Most of them inhibited hCA XII in the low nanomolar range, hCA IX with KIs ranging between 19 and 2482 nM, whereas they were poorly active against hCA II (KIs >10 μM) and hCA I (KIs ranging between 318 nM and 50 μM). Since hCA I and II are ubiquitous off-target isoforms, whereas the cancer-related isoforms hCA IX and XII were recently validated as drug targets, these results represent an encouraging achievement in the development of new anticancer candidates. Moreover, the lack of a classical zinc binding group in the structure of these inhibitors opens innovative, yet unexplored scenarios for different mechanisms of inhibition that could explain the high inhibitory selectivity. A computational approach has been carried out to further rationalize the biological data and to characterize the binding mode of some of these inhibitors. |
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| Keywords: | Saccharin Acesulfame Carbonic anhydrase inhibitor Cancer-related isoforms N/O-substitution |
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