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Article

Synthesis, Kinetic and Conformational Studies of 2-Substituted-5-(β-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase

by
Konstantinos F. Mavreas
1,
Dionysios D. Neofytos
2,
Evangelia D. Chrysina
2,*,
Alessandro Venturini
3,* and
Thanasis Gimisis
1,*
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
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(22), 5463; https://doi.org/10.3390/molecules25225463
Submission received: 20 October 2020 / Revised: 16 November 2020 / Accepted: 19 November 2020 / Published: 22 November 2020
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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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.
Keywords: type 2 diabetes; cancer; glycogen phosphorylase; catalytic site inhibitors; 5-(β-d-glucopyranosyl)pyrimidin-4-one synthesis; DFT conformational analysis type 2 diabetes; cancer; glycogen phosphorylase; catalytic site inhibitors; 5-(β-d-glucopyranosyl)pyrimidin-4-one synthesis; DFT conformational analysis

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MDPI and ACS Style

Mavreas, K.F.; Neofytos, D.D.; Chrysina, E.D.; Venturini, A.; Gimisis, T. Synthesis, Kinetic and Conformational Studies of 2-Substituted-5-(β-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase. Molecules 2020, 25, 5463. https://doi.org/10.3390/molecules25225463

AMA Style

Mavreas KF, Neofytos DD, Chrysina ED, Venturini A, Gimisis T. Synthesis, Kinetic and Conformational Studies of 2-Substituted-5-(β-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase. Molecules. 2020; 25(22):5463. https://doi.org/10.3390/molecules25225463

Chicago/Turabian Style

Mavreas, Konstantinos F., Dionysios D. Neofytos, Evangelia D. Chrysina, Alessandro Venturini, and Thanasis Gimisis. 2020. "Synthesis, Kinetic and Conformational Studies of 2-Substituted-5-(β-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase" Molecules 25, no. 22: 5463. https://doi.org/10.3390/molecules25225463

APA Style

Mavreas, K. F., Neofytos, D. D., Chrysina, E. D., Venturini, A., & Gimisis, T. (2020). Synthesis, Kinetic and Conformational Studies of 2-Substituted-5-(β-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase. Molecules, 25(22), 5463. https://doi.org/10.3390/molecules25225463

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