Synthesis of New Series of 2-C-(β-D-glucopyranosyl)-Pyrimidines and Their Evaluation as Inhibitors of Some Glycoenzymes

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Identification of C-β-d-Glucopyranosyl Azole-Type Inhibitors of Glycogen Phosphorylase That Reduce Glycogenolysis in Hepatocytes: In Silico Design, Synthesis, in Vitro Kinetics, and ex Vivo Studies

Several C-β-d-glucopyranosyl azoles have recently been uncovered as among the most potent glycogen phosphorylase (GP) catalytic site inhibitors discovered to date. Toward further exploring their translational potential, ex vivo experiments have been performed for their effectiveness in reduction of glycogenolysis in hepatocytes. New compounds for these experiments were predicted in silico where, for the first time, effective ranking of GP catalytic site inhibitor potencies using the molecular mechanics-generalized Born surface area (MM-GBSA) method has been demonstrated. For a congeneric training set of 27 ligands, excellent statistics in terms of Pearson (RP) and Spearman (RS) correlations (both 0.98), predictive index (PI = 0.99), and area under the receiver operating characteristic curve (AU-ROC = 0.99) for predicted versus experimental binding affinities were obtained, with ligand tautomeric/ionization states additionally considered using density functional theory (DFT). Seven 2-aryl-4(5)-(β-d-glucopyranosyl)-imidazoles and 2-aryl-4-(β-d-glucopyranosyl)-thiazoles were subsequently synthesized, and kinetics experiments against rabbit muscle GPb revealed new potent inhibitors with best Ki values in the low micromolar range (5c = 1.97 μM; 13b = 4.58 μM). Ten C-β-d-glucopyranosyl azoles were then tested ex vivo in mouse primary hepatocytes. Four of these (5a–c and 9d) demonstrated significant reduction of glucagon stimulated glycogenolysis (IC50 = 30–60 μM). Structural and predicted physicochemical properties associated with their effectiveness were analyzed with permeability related parameters identified as crucial factors. The most effective ligand series 5 contained an imidazole ring, and the calculated pKa (Epik: 6.2; Jaguar 5.5) for protonated imidazole suggests that cellular permeation through the neutral state is favored, while within the cell, there is predicted more favorable binding to GP in the protonated form

A multidisciplinary study of 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors: Computation, synthesis, crystallography and kinetics reveal new potent inhibitors

3-(β-d-Glucopyranosyl)-5-substituted-1,2,4-triazoles have been revealed as an effective scaffold for the development of potent glycogen phosphorylase (GP) inhibitors but with the potency very sensitive to the nature of the alkyl/aryl 5-substituent (Kun et al., Eur. J. Med. Chem. 2014, 76, 567). For a training set of these ligands, quantum mechanics-polarized ligand docking (QM-PLD) demonstrated good potential to identify larger differences in potencies (predictive index PI = 0.82) and potent inhibitors with K 's < 10 μM (AU-ROC = 0.86). Accordingly, in silico screening of 2335 new analogues exploiting the ZINC docking database was performed and nine predicted candidates selected for synthesis. The compounds were prepared in O-perbenzoylated forms by either ring transformation of 5-β-d-glucopyranosyl tetrazole by N-benzyl-arenecarboximidoyl chlorides, ring closure of C-(β-d-glucopyranosyl)formamidrazone with aroyl chlorides, or that of N-(β-d-glucopyranosylcarbonyl)arenethiocarboxamides by hydrazine, followed by deprotections. Kinetics experiments against rabbit muscle GPb (rmGPb) and human liver GPa (hlGPa) revealed five compounds as potent low μM inhibitors with three of these on the submicromolar range for rmGPa. X-ray crystallographic analysis sourced the potency to a combination of favorable interactions from the 1,2,4-triazole and suitable aryl substituents in the GP catalytic site. The compounds also revealed promising calculated pharmacokinetic profiles. [Abstract copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Synthesis of novel C-glycosyl heterocycles

In the course of my research numerous C-glucopyranosyl azoles and 2-glycopyranosyl pyrimidines were synthesized. An improved method for the preparation of 4(5)-aryl-2-(β-D-glucopyranosyl)imidazoles was elaborated. Methods for the synthesis of 2-aryl-4(5)-(β-D-glucopyranosyl)imidazoles, 2-aryl-4-(β-D-glucopyranosyl)thiazoles and C-glycosylated imidazo-fused heterocycles were developed. 2-(β-D-Glucopyranosyl)pyrimidines were obtained by Pinner type cyclocondensation of C-(β-D-glucopyranosyl)formamidines and 1,3-dielectrophiles. Among the newly prepared azoles effective glycogen phosphorylase inhibitors were found.Doktori munkám során új típusú C-glükopiranozil-azolokat és 2-glikopiranozil-pirimidineket állítottam elő. A korábbiaknál hatékonyabb eljárást dolgoztunk ki 4(5)-aril-2-(β-D-glükopiranozil)imidazolok szintézisére. Módszereket fejlesztettünk ki 2-aril-4(5)-(β-D-glükopiranozil)imidazolok, 2-aril-4-(β-D-glükopiranozil)tiazolok és anellált gyűrűs C-(β-D-glükopiranozil)imidazolok előállítására. 2-(β-D-Glükopiranozil)pirmidineket szintetizáltunk C-(β-D-glükopiranozil)formamidinek és 1,3-dielektrofilek Pinner-típusú reakciójával. Az előállított azolok között hatékony glikogén foszforiláz inhibitorokat találtunk.d

Synthesis of C-β-D-glucopyranosyl derivatives of some fused azoles for the inhibition of glycogen phosphorylase

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Improved preparation of 4(5)-aryl-2-(β-D-glucopyranosyl)-imidazoles, the most efficient glucose analogue inhibitors of glycogen phosphorylase

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C-(2-Deoxy-D-arabino-hex-1-enopyranosyl)-oxadiazoles: synthesis of possible isomers and their evaluation as glycogen phosphorylase inhibitors

Synthetic methods were elaborated for D-glucals attached to oxadiazoles by a C-C bond. Introduction of the double bond was effected by either DBU induced elimination of PhCOOH from the O-perbenzoylated glucopyranosyl precursors or Zn/N-methylimidazole mediated reductive elimination from the 1-bromoglucopyranosyl starting compounds. Alternatively, heterocyclizations of 2-deoxy-D-arabino-hex-1-enopyranosyl cyanide were also carried out. Test compounds were obtained by Zemplén debenzoylation, however, none of them showed significant inhibition of rabbit muscle glycogen phosphorylase b

The first general synthesis of 2-C-(β-D-glycopyranosyl)pyrimidines and their evaluation as inhibitors of some glycoenzymes

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