First Synthesis of 3-Glycopyranosyl-1,2,4-Triazines and Some Cycloadditions Thereof.

C-glycopyranosyl derivatives of six-membered heterocycles are scarcely represented in the chemical literature and the title 3-glycopyranosyl-1,2,4-triazines are completely unknown. In this paper, the first synthesis of this compound class is accomplished by the cyclocondensation of C-glycosyl formamidrazones and 1,2-dicarbonyl derivatives. In addition, the synthesis of C-glycopyranosyl 1,2,4-triazin-5(4H)-ones was also carried out by the transformation of the above formamidrazones with α-keto-carboxylic esters. Inverse electron demand Diels-Alder reactions of 3-glycopyranosyl-1,2,4-triazines with a bicyclononyne derivative yielded the corresponding annulated 2-glycopyranosyl pyridines.

Reactions of 1-C-acceptor-substituted glycals with nucleophiles under acid promoted (Ferrier-rearrangement) conditions.

The reactivity of O-peracetylated and O-perbenzoylated 1-COOMe, 1-CONH2 and 1-CN-substituted glycals was studied against O-, S-, N- and C-nucleophiles in the presence of Lewis acids. Allylic substituted products with exclusive axial stereoselectivity were formed with simple alcohols, N3-, and Cl- ions, but with benzyl thiol the Ferrier rearrangement took place and thioglycosides were obtained. The use of a sugar derived thiol resulted in the formation of both the allylic substituted and the rearranged products.

Coupling of N-tosylhydrazones with tetrazoles: synthesis of 2-ß-D-glycopyranosylmethyl-5-substituted-2H-tetrazole type glycomimetics.

Coupling reactions of O-peracylated 2,6-anhydro-aldose tosylhydrazones (C-(ß-d-glycopyranosyl)formaldehyde tosylhydrazones) with tetrazoles were studied under metal-free conditions using thermic or microwave activation in the presence of different bases. The reactions proved highly regioselective and gave the corresponding, up-to-now unknown 2-ß-d-glycopyranosylmethyl-2H-tetrazoles in 7-67% yields. The method can be applied to get new types of disaccharide mimetics, 5-glycosyl-2-glycopyranosylmethyl-2H-tetrazoles, as well. Galectin binding studies with C-(ß-d-galactopyranosyl)formaldehyde tosylhydrazone and 2-(ß-d-galactopyranosylmethyl)-5-phenyl-2H-tetrazole revealed no significant inhibition of any of these lectins.

Glycogen phosphorylase inhibitor, 2,3-bis[(2E)-3-(4-hydroxyphenyl)prop-2-enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells.

Type 2 diabetes mellitus (T2DM), one of the most common metabolic diseases, is characterized by insulin resistance and inadequate insulin secretion of ß cells. Glycogen phosphorylase (GP) is the key enzyme in glycogen breakdown, and contributes to hepatic glucose production during fasting or during insulin resistance. Pharmacological GP inhibitors are potential glucose lowering agents, which may be used in T2DM therapy. A natural product isolated from the cultured broth of the fungal strain No. 138354, called 2,3-bis(4-hydroxycinnamoyloxy)glutaric acid (FR258900), was discovered a decade ago. In vivo studies showed that FR258900 significantly reduced blood glucose levels in diabetic mice. We previously showed that GP inhibitors can potently enhance the function of ß cells. The purpose of this study was to assess whether an analogue of FR258900 can influence ß cell function. BF142 (Meso-Dimethyl 2,3-bis[(E)-3-(4-acetoxyphenyl)prop-2-enamido]butanedioate) treatment activated the glucose-stimulated insulin secretion pathway, as indicated by enhanced glycolysis, increased mitochondrial oxidation, significantly increased ATP production, and elevated calcium influx in MIN6 cells. Furthermore, BF142 induced mTORC1-specific phosphorylation of S6K, increased levels of PDX1 and insulin protein, and increased insulin secretion. Our data suggest that BF142 can influence ß cell function and can support the insulin producing ability of ß cells.

Synthetic, enzyme kinetic, and protein crystallographic studies of C-ß-d-glucopyranosyl pyrroles and imidazoles reveal and explain low nanomolar inhibition of human liver glycogen phosphorylase.

C-ß-d-Glucopyranosyl pyrrole derivatives were prepared in the reactions of pyrrole, 2-, and 3-aryl-pyrroles with O-peracetylated ß-d-glucopyranosyl trichloroacetimidate, while 2-(ß-d-glucopyranosyl) indole was obtained by a cross coupling of O-perbenzylated ß-d-glucopyranosyl acetylene with N-tosyl-2-iodoaniline followed by spontaneous ring closure. An improved synthesis of O-perbenzoylated 2-(ß-d-glucopyranosyl) imidazoles was achieved by reacting C-glucopyranosyl formimidates with α-aminoketones. The deprotected compounds were assayed with isoforms of glycogen phosphorylase (GP) to show no activity of the pyrroles against rabbit muscle GPb. The imidazoles proved to be the best known glucose derived inhibitors of not only the muscle enzymes (both a and b) but also of the pharmacologically relevant human liver GPa (Ki = 156 and 26 nM for the 4(5)-phenyl and -(2-naphthyl) derivatives, respectively). An X-ray crystallographic study of the rmGPb-imidazole complexes revealed structural features of the strong binding, and also allowed to explain the absence of inhibition for the pyrrole derivatives.

Syntheses and transformations of α-azido ketones and related derivatives.

Organic azides are known and utilized in the synthetic organic chemistry as amine precursors, potential sources of nitrenes, dipoles useful in 1,3-dipolar cycloadditions and starting materials of phosphoranes for a long time, and their literature has been overviewed by several authors. On the other hand, there are some special subclasses within the azides which possess peculiar and interesting properties differing from those of the majority and offering extra synthetic possibilities. In this critical review we wish to give an exhaustive overview on the synthesis and synthetic potential of α-azido ketones and related systems, an underestimated group of compounds. The enhanced acidity of the α-hydrogen offers various new synthetic applications including the creation of a new C-C bond, while the joint presence of the carbonyl and vinyl functions of α-azido-α,ß-unsaturated ketones results in a special reactivity, too. Chemo- and stereoselectivity issues also represent important points which are discussed in detail. Finally, the usefulness of the titled derivatives in the synthesis of various heterocycles is reviewed (273 references).