New coumarin/sulfocoumarin linked phenylacrylamides as selective transmembrane carbonic anhydrase inhibitors: Synthesis and in-vitro biological evaluation |
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| Institution: | 1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India;2. Department of Chemistry, Anwarul Uloom College, 11-3-918, New Malleypally, Hyderabad 500001, T. S., India;3. Università degli Studi di Firenze, Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto, Fiorentino, Florence, Italy;1. School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China;2. Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China;3. Shandong Peninsula Engineering Research Center of Comprehensive Brine Utilization, Weifang University of Science and Technology, Weifang 262700, Shandong, China;4. Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China;1. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA;2. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA;3. Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, USA;4. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA;5. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA;1. La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia;2. School of Science, University of New South Wales, Canberra 2610, Australia;3. School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia;4. Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia;5. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia |
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| Abstract: | Two novel series of phenylacrylamide linked coumarins and sulfocoumarins (6a-p, 8a-i, and 14a-g) were synthesized and evaluated against four physiologically relevant human carbonic anhydrases (hCAs, EC 4.2.1.1), isoforms hCA I, hCA II, hCA IX and hCA XII for their inhibitory action. All new compounds when screened for carbonic anhydrase inhibitory activity have shown selective inhibition towards the tumor associated isoforms hCA IX and XII over CA I and II, with inhibition constants in the submicromolar to low nanomolar range. Compound 6b and 14g exhibited significant inhibition with low nanomolar potency against hCA IX, whereas 6k was effective against hCA XII. Compounds 6b, 14g and 6k may be considered as lead molecules for future development of cancer therapeutics based on a novel mechanism of action. |
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| Keywords: | Carbonic anhydrase Phenylacrylamide Coumarin Sulfocoumarin hCA IX XII isoform Hypoxia tumor |
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