Structural modifications of 2,3-indolobetulinic acid: Design and synthesis of highly potent α-glucosidase inhibitors |
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| Institution: | 1. Ufa Institute of Chemistry UFRS RAS, 71 pr. Oktyabrya, Ufa 450054, Russian Federation;2. Bashkir State University, 32 Validy Str., Ufa 450076, Russian Federation;3. Institute of Chemistry, Vietnamese Academy of Science and Technology, 18 Hoang Quoc Viet Str., Cau Giay Dist., Hanoi, Viet Nam;4. Scientific Center for Innovative Drugs, Volgograd State Medical University, Novorossiyskaya st. 39, Volgograd 400087, Russian Federation;1. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;2. Pakistan Academy of Sciences, 3-Constitution Avenue G-5/2, Islamabad, Pakistan;3. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia;4. Endocrinology & Metabolism Research Institute (EMRI), Tehran University of Medical Sciences, Tehran, Iran;5. Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, 250 Princes Highway, Werribee, Victoria 3030, Australia;6. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;7. PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan;8. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;1. Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan;2. Department of Biotechnology, Kinnaird College for Women, Lahore 54000, Pakistan;3. Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan;4. Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan;5. Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan;1. Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, 81746-73461, Isfahan, Iran;2. Food and Drug Research Institute, Food and Drug Administration, MOHE, Tehran, Iran;3. Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran;4. School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran;5. School of Chemistry, Shahrood University of Technology, Shahrood, Iran;6. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran;1. Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;2. Persian Medicine and Pharmacy Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;3. Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran;4. School of Chemistry, College of Science, University of Tehran, Tehran, Iran;5. Faculty of Pharmacy, International Campus (TUMS-IC), Tehran University of Medical Sciences, Tehran, Iran;6. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran 1417614411, Iran;7. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran;8. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;1. Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan;2. Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan;3. Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan;4. Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan;1. Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Postal Code 616, Birkat Al Mauz, Nizwa, Oman;2. Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, d-06120 Halle (Saale), Germany |
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| Abstract: | A series of nineteen nitrogen-containing lupane triterpenoids was obtained by modification of C2, C3, C20 and C28 positions of betulonic acid and their α-glucosidase inhibiting activity was investigated. Being a leader compound from our previous study, 2,3-indolo-betulinic acid was used as the main template for different modifications at C-(28)-carboxyl group to obtain cyano-, methylcyanoethoxy-, propargyloxy- and carboxamide derivatives. 20-Oxo- and 29-hydroxy-20-oxo-30-nor-analogues of 2,3-indolo-betulinic acid were synthesized by ozonolysis of betulonic acid followed by Fischer indolization reaction. To compare the influence of the fused indole or the seven-membered A-ring on the inhibitory activity, lupane A-azepanones with different substituents at C28 were synthesized. The structure-activity relationships revealed that the enzyme inhibition activity dramatically increased (up to 4730 times) when the carboxylic group of 2,3-indolo-betulinic acid was converted to the corresponding amide. Thus, the IC50 values for glycine amide and L-phenylalanine amides were 0.04 and 0.05 μM, respectively. This study also revealed that 2,3-indolo-platanic acid is 4.5 times more active than the parent triterpenoid with IC50 of 0.4 μM. Molecular modeling suggested that improved potency is due to additional polar interactions formed between C28 side chain and a sub-pocket of the α-glucosidase allosteric site. |
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| Keywords: | Natural products Lupanes Triterpenoids Betulinic acid Indole Synthesis Type II diabetes α-Glucosidase inhibitor Acarbose |
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