Synthesis of novel l-rhamnose derived acyclic C-nucleosides with substituted 1,2,3-triazole core as potent sodium-glucose co-transporter (SGLT) inhibitors |
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| Institution: | 1. Organic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;2. Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;3. Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;1. Nutritional Biochemistry Research Laboratory, Department of Biochemistry, University of Ilorin, Ilorin, Nigeria;2. Antioxidants, Free Radicals, Functional Foods and Toxicology Research Laboratory, Department of Biological Sciences, Al-Hikmah University, Ilorin, Nigeria;3. Antioxidants, Free Radicals and Toxicology Research Laboratory, Biochemistry and Nutrition Unit, Department of Chemical Sciences, Fountain University, Osogbo, Nigeria;1. Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico;2. Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico;3. Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA;4. Endocrinology Unit, Centre for Cardiovascular Science, The Queen''s Medical Research Institute, University of Edinburgh, EH16 4TJ, UK;5. Facultad de Química, Universidad Autónoma de Yucatán, Mérida, Yucatán 97150, Mexico;6. Instituto de Química Aplicada, Universidad del Papaloapan, Tuxtepec, Oaxaca 68301, Mexico;1. Department of Pharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Mayurbhanj 757086, Odisha, India;2. Department of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Koni, Bilaspur 495 009, C.G., India;1. Department of Chemistry, GC University, Lahore 54000, Pakistan;2. Interdisciplinary Research Center in Biomedical Materials, COMSATS Institute of Information Technology, Lahore 54000, Pakistan;3. Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan;4. Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad 44000, Pakistan;5. Department of Chemistry, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal;1. Preclinical Research, Max Zeller Soehne AG, Romanshorn, Switzerland;2. RenaSci Ltd., Nottingham, UK |
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| Abstract: | Sodium-glucose co-transporter (SGLT) inhibitors are a novel class of therapeutic agents for the treatment of type 2 diabetes by preventing renal glucose reabsorption. In our efforts to identify novel inhibitors of SGLT, we synthesized a series of l-rhamnose derived acyclic C-nucleosides with 1,2,3-triazole core. The key β-ketoester building block 4 prepared from l-rhamnose in five steps, was reacted with various aryl azides to produce the respective 1,2,3-triazole derivatives in excellent yields. Deprotection of acetonide group gave the desired acyclic C-nucleosides 7a–o. All the new compounds were screened for their sodium-glucose co-transporters (SGLT1 and SGLT2) inhibition activity using recently developed cell-based nonradioactive fluorescence glucose uptake assay. Among them, 7m with IC50: 125.9 nM emerged as the most potent SGLT2 inhibitor. On the other hand compound 7d exhibited best selectivity for inhibition of SGLT2 (IC50: 149.1 nM) over SGLT1 (IC50: 693.2 nM). The results presented here demonstrated the utility of acyclic C-nucleosides as novel SGLT inhibitors for future investigations. |
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| Keywords: | Triazole Rhamnose Diabetes Click chemistry SGLT2 inhibitors |
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