Design,synthesis and evaluation of N-substituted saccharin derivatives as selective inhibitors of tumor-associated carbonic anhydrase XII |
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| Affiliation: | 1. Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy;2. Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy;3. Università degli Studi di Firenze, Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, Via U. Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;1. Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400, Serdang, Selangor Darul Ehsan, Malaysia;2. Research Centre for Crystalline Materials, School of Science and Technology, Sunway University, 47500, Bandar Sunway, Selangor Darul Ehsan, Malaysia;3. Medical Genetics Laboratory, Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor Darul Ehsan, Malaysia;1. Faculty of Light Industry and Chemical Engineering, Dalian Polytechnic University, Dalian 116034, China;2. Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, 44 West Wenhua Rd, Ji’nan 250012, PR China;2. Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, Madison 53705, USA;1. Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden;2. School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland;3. Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FI- 00014 Helsinki, Finland;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 |
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| Abstract: | A series of N-alkylated saccharin derivatives were synthesized and tested for the inhibition of four different isoforms of human carbonic anhydrase (CA, EC 4. 2.1.1): the transmembrane tumor-associated CA IX and XII, and the cytosolic CA I and II. Most of the reported derivatives inhibited CA XII in the nanomolar/low micromolar range, hCA IX with KIs ranging between 11 and 390 nM, whereas they were inactive against both CA I (KIs >50 μM) and II (KIs ranging between 39.1 nM and 50 μM). Since CA I and II are off-targets of antitumor carbonic anhydrase inhibitors (CAIs), the obtained results represent an encouraging achievement for the development of new anticancer candidates without the common side effects of non-selective CAIs. Moreover, the lack of an explicit zinc binding function on these inhibitors opens the way towards the exploration of novel mechanisms of inhibition that could explain the high selectivity of these compounds for the inhibition of the transmembrane, tumor-associated isoforms over the cytosolic ones. |
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| Keywords: | Saccharin Selective carbonic anhydrase XII inhibitors Cyclic tertiary sulfonamides |
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