Synthesis of N-Glucopyranosidic Derivatives as Potential Inhibitors that Bind at the Catalytic Site of Glycogen Phosphorylase

T.      Gimisis

doi:10.2174/1389557511009011127

Abstract

Glycogen phosphorylase (GP) is a promising molecular target for the treatment of Type 2 diabetes. The design of potential inhibitors for the catalytic site of the enzyme is based on the high affinity for β-D-glucopyranose and the presence of a β-cavity that extends from the sugar anomeric position forming a 15 x 7.5 x 10 A available space. This review is focused on our efforts towards the design and synthesis of various families of potential inhibitors, including N-β-Dglucopyranosyl oxamic acid esters and oxamides, N-β-D-glucopyranosylaminocarbonyl L-aminoacids and peptides, as well as glucose-derived purine and pyrimidine nucleosides, spiro- and other bicyclic derivatives. Kinetic and crystallographic study of the interactions of these inhibitors with GP has increased our understanding of the importance of the various functional groups within the catalytic site and has pointed the way towards the in silico prediction and design of potent inhibitors, which are both synthetically viable and pharmacologically relevant.

Keywords: N-β-D-glucopyranosyl oxamic acid esters and oxamides, N-β-D-glucopyranosylaminocarbonyl-L-aminoacids, purine and pyrimidine nucleosides, glycogen phosphorylase, synthetic inhibitors, N-Glucopyranosidic Derivatives, Type 2 diabetes, D-glucopyranose, glucopyranosyl oxamic acid esters and oxamides, glycogenolysis, glu-cose-1-phosphate, pyridoxal-5'-phosphate, cavity, carbonyl of His377, QSAR studies, D-glucose-1-phosphate, Ki values, heteroatom links, Steyermark's ox-azolidinone, urea-tethered neoglucoconjugates, L-amino acids, triethylamine salts, HPLC, NMR, Ala-Ala dipeptide conjugate, solid-phase synthesis, Rink amide, Fmoc strategy, single-alanine conjugate, CYCLIC DERIVATIVES, stacks, Tyr613, Phe285, catalytic site, regiospecific synthesis, regio-selectivity, oxida-tive deamination, acetolysis, Vorbrüggen N-glycosylation, Fractional crystallization, TMSOTf, Acetylation, silylation, kinetic studies, pyrimidine ring, silylated bases, micromolar inhibition constants, D-glucopyranosylidene-spiro-hydantoin, autooxidation, Tetrazolo-pyrimidines, 13C NMR spectroscopy, thermo-dynamic product, free amidic nitrogen, bioavailability, glycogen phosphorylase inhibitors