Synthesis,Kinetic and Conformational Studies of 2-Substituted-5-(β-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase |
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Authors: | Konstantinos F. Mavreas Dionysios D. Neofytos Evangelia D. Chrysina Alessandro Venturini Thanasis Gimisis |
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Affiliation: | 1.Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15784 Athens, Greece;2.Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece;3.Istituto ISOF, Consiglio Nazionale delle Ricerche, 40129 Bologna, Italy |
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Abstract: | Dysregulation of glycogen phosphorylase, an enzyme involved in glucose homeostasis, may lead to a number of pathological states such as type 2 diabetes and cancer, making it an important molecular target for the development of new forms of pharmaceutical intervention. Based on our previous work on the design and synthesis of 4-arylamino-1-(β-d-glucopyranosyl)pyrimidin-2-ones, which inhibit the activity of glycogen phosphorylase by binding at its catalytic site, we report herein a general synthesis of 2-substituted-5-(β-d-glucopyranosyl)pyrimidin-4-ones, a related class of metabolically stable, C-glucosyl-based, analogues. The synthetic development consists of a metallated heterocycle, produced from 5-bromo-2-methylthiouracil, in addition to protected d-gluconolactone, followed by organosilane reduction. The methylthio handle allowed derivatization through hydrolysis, ammonolysis and arylamine substitution, and the new compounds were found to be potent (μM) inhibitors of rabbit muscle glycogen phosphorylase. The results were interpreted with the help of density functional theory calculations and conformational analysis and were compared with previous findings. |
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Keywords: | type 2 diabetes, cancer, glycogen phosphorylase, catalytic site inhibitors, 5-(β -d-glucopyranosyl)pyrimidin-4-one synthesis, DFT conformational analysis |
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