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

Abstract

Despite the substantial interest in C-glycosyl heterocycles as mimetics of biologically active native glycans, the appearance of C-glycopyranosyl derivatives of six-membered heterocycles, both in synthetic and biological contexts, is rather scarce. As part of our ongoing research program aimed at preparing hitherto barely known 2-C-glycopyranosyl pyrimidines, the goal of the present study was to synthesize new 5-mono- and multiply substituted derivatives of this compound class. Thus, 2-C-(β-D-glucopyranosyl)-5,6-disubstituted-pyrimidin-4(3H)-ones and 4-amino-2-C-(β-D-glucopyranosyl)-5,6-disubstituted-pyrimidines were prepared by base-mediated cyclocondensations of O-perbenzylated and O-unprotected C-(β-D-glucopyranosyl) formamidine hydrochlorides with methylenemalonic acid derivatives. The 2-C-(β-D-glucopyranosyl)-5-substituted-pyrimidines were obtained from the same amidine precursors upon treatment with vinamidinium salts. The deprotected derivatives of these pyrimidines were tested as inhibitors of some glycoenzymes. None of them showed inhibitory activity towards glycogen phosphorylase and α- and β-glucosidase enzymes, but some members of the sets exhibited moderate inhibition against bovine liver β-galactosidase.

Dual-Target Compounds against Type 2 Diabetes Mellitus: Proof of Concept for Sodium Dependent Glucose Transporter (SGLT) and Glycogen Phosphorylase (GP) Inhibitors

“…In recent papers [ 62 , 63 ], the O -perbenzylated C -(β-D-glucopyranosyl)formamidine hydrochloride 14 [ 64 , 65 ] was shown to be a suitable precursor for Pinner-type synthesis of variously substituted 2-(β-D-glucopyranosyl)pyrimidines. Based on these preliminaries, the preparation of 4-arylmethyl-2-(β-D-glucopyranosyl)pyrimidines was also envisaged by base-mediated cyclocondensations of 14 .…”

Synthesis of new allylidene amino phenol-containing Schiff bases and metal complex formation using trimethinium salts

“…At rst, compounds 1 were prepared similar to the previous studies. [18][19][20][21][22][23][24][25] Then the results were treated with aminophenol derivatives to afford the related Schiff base ligands as the desired products. As Table 2 indicates, a variety of trimethinium salts were successfully applied in this process to afford the corresponding Schiff base ligands derivatives as novel compounds with excellent yields.…”

“…One of the useful attributes of many vinamidinium salts is their ease of preparation from substituted acetic acids under Vilsmeier-Haack conditions. [12][13][14][15][16][17][18][19][20][21][22][23] "In this study, our research group was able to prepare bsubstituted trimethinium salts with different R groups (including aryls and heteroaryls) from correspondingly substituted acetic acids, R-CH 2 CO 2 H, with good yields". 24,25 In continuation of this research on applications of trimethinium salts in organic synthesis (Scheme 1), [26][27][28][29][30][31] in this study, we report a new and highly efficient method for the synthesis of a novel class of allylidene amino phenol-containing Schiff bases from the reaction of trimethinium salts and diverse aminophenols in the presence of triethylamine, under catalyst-free conditions in EtOH at reux (Scheme 2).…”

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

“…It is useful to compare the activity of these new, C -glycosyl pyrimidin-4-one derivatives with the structurally related 2-(glucosyl)pyrimidin-4-ones [ 57 , 58 ], recently reported to exhibit no activity towards RMGP. The 4-carbonyl group of the compounds synthesized herein ( 4 , 5 , 6 ), positioned ortho to the C -glycosyl bond, is expected to be pointing in the same direction as was observed for the 2-carbonyl group of GLAC ( Figure 2 and Figure 6 ).…”

“…In the crystal structure of the RMGP:GLAC complex [ 25 ], this carbonyl forms water-mediated interactions with the carboxylates of Glu 88 and Asp 283. We believe that these interactions are crucial for binding, since, in the case of 2-(glucosyl)pyrimidin-4-ones, where this carbonyl group is replaced by a pyrimidine nitrogen, no activity is observed [ 57 , 58 ].…”