Synthesis and antihyperlipidemic activity of novel glycosyl fructose derivatives

A series of novel di and trisaccharide derivatives containing d-fructose moiety at the reducing end have been synthesized and evaluated for their antihyperlipidemic activity in hyperlipidemic hamster model. Among 11 glycosyl fructose derivatives five compounds showed potent antihyperlipidemic activity either by enhancing high-density lipoprotein (HDL) cholesterol concentration and/or lowering triglyceride (TG) level.     

Significant rate accelerated synthesis of glycosyl azides and glycosyl 1,2,3-triazole conjugates

An efficient and significantly rapid access of a series of glycosyl azides and glycosyl 1,2,3-triazole conjugates is reported using modified one-pot reaction conditions. In both cases yields were excellent and single diastereomers were obtained. Figure Rapid preparation of 4-substituted glycosyl 1,2,3-triazole conjugates from glycosyl bromides. CDRI communication no. 7340.     

2'-Carboxybenzyl glycosides: glycosyl donors for C-glycosylation and conversion into other glycosyl donors

Glycosylation of various glycosyl acceptors with 2'-carboxybenzyl (CB) 2,3,4,6-tetra-O-benzyl-beta-D-glucopyranoside and CB 2,3,4,6-tetra-O-benzyl-alpha-D-mannopyranoside as glycosyl donors afforded alpha-C-glycosides exclusively or predominantly in good yields. CB glycosides were also converted to other well-known glycosyl donors, the corresponding phenyl thioglycoside and the glycosyl fluoride derivatives.     

Synthesis and surface-active properties of glycosyl carbamates and thioureas

Several amphiphilic glycosyl carbamates, glycosyl thiocarbamates and glycosylthioureas were prepared by addition of the anomeric hydroxyl group of acetylated glycosyl derivatives to alkyl isocyanates, or by reaction of glycosyl isothiocyanates with alcohols or amines. The solubility, critical micelle concentrations and detergent efficiency for the extraction of proteins of these compounds were evaluated and compared.     

Convenient syntheses of symmetrical and unsymmetrical glycosyl carbodiimides and N,N-bis(glycosyl)cyanamides

Reaction of glycosyl trimethylphosphinimides with carbon disulfide under mild conditions (room temperature, short reaction time) leads to symmetrical glycosyl carbodiimides. Addition of bis(trimethylsilyl)carbodiimide to peracetylated aldoses under the influence of SnCl(4) afforded N,N-bis(glycosyl)cyanamides for the first time. Readily accessible unsymmetrical N,N'-bis(glycosyl)thioureas can be desulfurated and transformed into the corresponding carbodiimides using HgO in CHCl(3)/water at room temperature.     

8-Alkylaminoadenyl nucleotides as probes of dehydrogenase interactions with nucleotide analogs of different glycosyl conformation.

The nucleotides 8-amino-, 8-methylamino-, and 8-dimethylaminoadenylic acid have been synthesized and their preferred conformations about the glycosyl bond in qaueous solution have been determined by 1H nuclear magnetic resonance spectroscopy. Paramagnetic relaxation studies, nuclear Overhauser enhancement measurements, chemical shifts, and coupling constant comparisons indicate that their is rotation about the glycosyl bond and that preference for either the anti or syn conformation depends on the extent of alkyl substitution on the 8-amino group. The primary and secondary amines 8-amino- and 8-methylaminoadenylic acid adopt a perferential anti conformation about the glycosyl bond, while the tertiary amine 8-dimethylaminoadenylic acid exists predominantly in the syn form. These three analogs provide a system to study interactions of a dehydrogenase with coenzyme inhibitors having different glycosyl conformer populations. All three analogs are competitive inhibitors of NADH in reaction with chicken muscle lactate dehydrogenase, and the Ki values show little dependence on the nature of the amino substitution. This demonstrates that the distribution of conformations about the nucleotide glycosyl bond does not effect the competition of the nucleotide for lactate dehydrogenase apoenzyme. Several models for enzyme-coenzyme binding are discussed. The available data cannot distinguish whether the enzyme binds nucleotide in both the anti and syn conformations or in purely the anti conformation. However, at some stage of the enzyme-coenzyme interaction, there appears to be a strong stabilization of the nucleotide in the anti conformation about the glycosyl bond.     

Appel-Lee synthesis of glycosyl inositols, substrates for inositol dehydrogenase from Bacillus subtilis

We recently reported that inositol dehydrogenase (EC 1.1.1.18) from Bacillus subtilis can catalyze the highly stereoselective oxidation of 1l-4-O-substituted myo-inositol derivatives, as well as disaccharides melibiose and isomaltose, but not gentiobiose or maltose, consistent with the requirement of an alpha-(1-->6) linkage. We believed that the enzyme might therefore catalyze efficient stereoselective oxidation of the appropriate alpha-linked glycosyl inositols. We have synthesized alpha-D-glucopyranosyl-(1-->4)-(DL)-myo-inositol and alpha-d-galactopyranosyl-(1-->4)-(DL)-myo-inositol using the Appel-Lee protocol to couple benzyl-protected glycosyl donors to protected inositols. This method failed in our hands using glycosyl donors derived from D-mannose and 2-azido-2-deoxy-D-glucose. When myo-inositol 1,3,5-monoorthoformate is used as the acceptor, the reaction is regiospecific for the 4/6-position. We report here the mildest conditions known for the removal of the orthoformate group. 2-Azido-2-deoxy-alpha-D-glucopyranosyl-(1-->4)-(DL)-myo-inositol was synthesized using the trichloroacetimidate derivative as the donor, and all three pseudo-disaccharides were substrates for inositol dehydrogenase. The glucopyranosyl and galactopyranosyl derivatives displayed apparent second-order rate constants comparable to that of myo-inositol.     

Methods of synthesis of glycosyl fluorides

In recent years glycosyl fluorides have been utilized as versatile sugar donors in the synthesis of natural products and carbohydrates. This paper provides an update on the advances made in the preparation of glycosyl fluorides during the last decade (1988-1998).     

Molecular design, synthesis and bioactivity of glycosyl hydrazine and hydrazone derivatives: notable effects of the sugar moiety

Assuming that the water solubility of our previous hydrazone derivatives would improve after modification with sugars while keeping or modulating their notable biological activities, we designed and synthesized some glycosyl hydrazine and hydrazone derivatives. Bioassay results indicated that the antitumor activity of our previously prepared hydrazones reduced or disappeared after modification with sugars. On the contrary, some glycosyl derivatives displayed much better antifungal activity against selected fungi. Obviously, a small sugar can change the biological activity of hydrazones significantly.     

Stereoselective syntheses of phosphorylated and sulfated glycosyl serines in glycosaminoglycan for biological probes.

Phosphorylated glycosyl serines of glycosaminoglycan with/without sulfate: beta-D-Xyl(2P)-Ser (1) and beta-D-Gal(+/-6S)-(1->4)-beta-D-Xyl(2P)-Ser (2, 3) were suitably designed for biological probes. These oligosaccharides were synthesized in a stereocontrolled manner.     

Synthesis of glycosyl esters of oleanolic acid

The trisaccharide, O-(2,3,4-tri-O-benzoyl-β-L-rhamnopyranosyl)-(1→4)-O-(2,3,6-tri-O-benzoyl-β-D-glucopyranosyl)-(1→6)-1,2,3,4-tetra-O-acetyl-β-D-glucopyranose has been prepared by two different routes. Condensation of this trisaccharide with oleanolic acid afforded the corresponding 1,2-trans glycosyl ester. Some other glycosyl esters of oleanolic acid were also prepared by the same method.     

Alkylating agents from sugars: synthesis of chlorambucil derivatives carried by chiral glycosyl glycerols derived from D-glucosamine

Chlorambucilamide derivatives involving chiral glycosyl glycerols derived from D-glucosamine were synthesized in good yield by coupling the chlorambucil moiety to the amino group of omega-amino-(omega-1)-hydroxyalkyl 2-acylamino-4,6-O-benzylidene-2-deoxy-beta-D-glucopyranosides, and subsequent hydrolysis of the benzylidene group. The starting material was easily available from 2-acetamido-2-deoxy-D-glucose. The bonding of 2,3,4,6-tetra-O-pivaloyl-beta-D-galactopyranosylamine to chlorambucil by formation of an amide function is also described.     

Use of ionically tagged glycosyl donors in the synthesis of oligosaccharide libraries

We have developed a new procedure based on the random glycosyl reaction of a partially benzoylated glycosyl acceptor with a glycosyl donor containing a 4,6-O-(4-methoxycarbonylbenzylidene) protecting group as a masked/caged ion-tag. Glycosylated products are ionically tagged by saponification of the methyl ester and the use of this anion-tag greatly simplifies the separation of the desired oligosaccharides from unreacted or excess glycosyl acceptors as well as from over-glycosylated oligosaccharides. In addition, the use of partially benzoylated acceptors greatly improves their solubility in dichloromethane increasing the yield of product formation and, also, of altering the distribution of positional isomers in favor of products derived by reaction of the donors at hydroxyl groups which otherwise would be considerably less reactive. Using this new approach in random glycosyl reactions, several oligosaccharide libraries were readily prepared in overall yields of 60–70% and the individual positional isomers present in the libraries were identified using the ‘reductive-cleavage’ method.     

The hydrolysis of glycosyl fluorides by glycosidases

1. alpha-d- and beta-d-Glucopyranosyl, alpha-d- and beta-d-galactopyranosyl, alpha-d-mannopyranosyl and alpha-d-xylopyranosyl fluorides were hydrolysed specifically by the respective glycosidases from several sources. 2. Use of specific inhibitors with a mixture of glycosidases from Helix pomatia intestinal juice showed that each glycosyl fluoride was hydrolysed only by the respective glycosidase. alpha-d-Glucopyranosidase and alpha-d-xylopyranosidase activities were shown to be due to different enzymes. 3. Partially purified enzyme preparations containing only one of the glycosidase activities hydrolysed only the corresponding glycosyl fluoride. 4. The configuration at C-1 of alpha-d-mannopyranosyl fluoride was confirmed since it was hydrolysed by an alpha-d-mannosidase preparation that contained no detectable beta-d-mannosidase activity. 5. An attempt to prepare o-nitrophenyl beta-d-mannopyranoside led only to o-nitrophenyl alpha-d-mannopyranoside.     

Natural phosphoglycans containing glycosyl phosphate units: structural diversity and chemical synthesis

An anomeric phosphodiester linkage formed by a glycosyl phosphate unit and a hydroxyl group of another monosaccharide is found in many glycopolymers of the outer membrane in bacteria (e.g., capsular polysaccharides and lipopolysaccharides), yeasts and protozoa. The polymers (phosphoglycans) composed of glycosyl phosphate (or oligoglycosyl phosphate) repeating units could be chemically classified as poly(glycosyl phosphates). Their importance as immunologically active components of the cell wall and/or capsule of numerous microorganisms upholds the need to develop routes for the chemical preparation of these biopolymers. In this paper, we (1) present a review of the primary structures (known to date) of natural phosphoglycans from various sources, which contain glycosyl phosphate units, and (2) discuss different approaches and recent achievements in the synthesis of glycosyl phosphosaccharides and poly(glycosyl phosphates).     

Synthesis, characterization, and cytotoxicity of some novel glycosyl thiazol-2-imines as antitumoral agents

A series of novel glycosyl thiazol-2-imines (3a-g) have been synthesized regioselectively in good yields from the hydrolysis of thiazol-2(3H)-imine-linked glycoconjugates. The glycosyl thiazol-2-imines were evaluated for their antitumor activity against Hela (cervical carcinoma), HCT-8 (colon carcinoma) and Bel-7402 (liver carcinoma). Among the compounds screened, 1-benzoyl-4-(4-nitrophenyl)-3-β-d-glucopyranosyl-thiazol-2(3H)-imine (3c) was found to be the most active compound against HCT-8.     

Mild one-pot preparation of glycosyl bromides

Mild one-pot protocols for the preparation of glycosyl bromides and alkyl bromides via in situ generation of HBr is reported here.     

Quantitative determination of the neutral glycosyl ceramides in human blood

A method is described for the qualitative and quantitative estimation of four neutral glycosyl ceramides from human plasma and erythrocytes. Total lipids extracted from 50 ml of plasma or packed erythrocytes were separated by silicic acid chromatography into neutral lipids, a fraction of mixed glycolipids that was eluted with acetone-methanol 9:1, and phospholipids. After mild alkali-catalyzed methanolysis to remove contaminants from the crude fraction of glycolipids, individual glycosyl ceramides were isolated by preparative thin-layer chromatography. The oligosaccharide portions of these lipids were characterized by cleavage with methanolic hydrogen chloride and gas chromatography of the O-trimethylsilyl methyl glycosides. It was possible to study the composition of the carbohydrate and sphingolipid base fractions in the same gas chromatographic analysis. With mannitol as an internal standard for gas chromatographic estimation of glucose, concentrations of each of the glycosyl ceramides were determined with a precision of about 10%. Recoveries of the lipids from plasma varied with the complexity of the oligosaccharide moiety and ranged from 94% with glucosyl ceramide to 71% with globoside. Concentrations of the four glycosyl ceramides in plasma and in erythrocytes were determined for samples from young, healthy males. Amounts of glycolipid as low as 0.1 micromole can be determined conveniently by this procedure.     

Design,synthesis and biological evaluation of azithromycin glycosyl derivatives as potential antibacterial agents

A series of 11,12-cyclic carbonate azithromycin-4″-O-carbamoyl glycosyl derivatives were designed, synthesized, and evaluated as antibacterial agents to search for target compounds with excellent activity. The results of preliminary antibacterial tests against eight strains in vitro revealed that all of the title compounds exhibited improved activities with broad spectrum compared with the parent compound. The glycosylated side chains may be the pharmacophores responsible for the improved activity.     

Composition of phosphoglycerides and glycosyl glycerides in castor bean mitochondria

Phosphoglycerides and glycosyl glycerides in mitochondria fromcastor bean endosperms were determined by silicic acid columnchromatography using C-A and C-M as eluting solvents and bysupplemental use of TLC. The small amount of glycosyl glyceridedetected in the mitochondrial fraction may be due to contaminationby other organelle(s). ¹Present address: Ocean Research Institute, University of Tokyo,Nakano, Tokyo 164, Japan. (Received June 13, 1974; )