Transition Metal Mediated Approaches To Cglycosides

Several years ago transition metal mediated reactions in the area of C-glycoside synthesis were primarily limited to palladium and to a lesser extent nickel and manganese. Over the last few years several other metals, including chromium, molybdenum, tungsten, cobalt, and rhodium, have been utilized in C-glycoside synthesis. This section discusses the chemistry of palladium, which is divided into Stille-type couplings and 77-allyl complexes. This is followed by considerations of the chemistry of...

The Unnatural Substrate Tolerance of the Enzymes Involved in Sialic Acid Biosynthesis

The possibility that sialic acid biosynthesis might be amenable to interception with unnatural substrates was first suggested by studies of the individual enzymes in the pathway. Several groups have analyzed the tolerance of various enzymes for unnatural substrates, revealing sites on metabolic intermediates at which functional group substitutions might be tolerated. Of the enzymes involved in sialic acid biosynthesis, the two that have attracted the most attention are CMP-Neu5Ac-synthetase and...

Ho

Formyl Acetals

Figure 8 Fisher glycosylation route (25). Figure 9 Synthesis of commonly employed D-arabinofuranosyl donors. Figure 9 Synthesis of commonly employed D-arabinofuranosyl donors. Figure 10 Synthesis of 8-galactofuranosides from acylic S,0-sugar acetals. Figure 10 Synthesis of 8-galactofuranosides from acylic S,0-sugar acetals. Ozonolysis of 3,4,6-tri-O-acetyl D-glucal (40), followed by reductive workup with dimethyl sulfide, affords the formyl aldehyde 41. The formate ester can be selectively...

Info

Contrary to the results in vitro, the 3-fluoro derivatives were relatively inactive in vivo, increasing life span by only 14 at 100 mg kg. 4-Fluoro-GalNAc, on the other hand, exhibited antitumor activity, increasing the life span of mice by 68 when administered a dosage of 50 mg kg1 d_1 for 5 consecutive days. Since GalNAc is primarily contained in O-linked structures (Fig. 5) this might reflect an important role for O-linked glycoproteins in tumor growth. Despite the...

Experimental Section A Pectin Glycerol Ester

HM-pectin (1 g, 73 DE, GENU) was partially swollen in 20 mL of glycerol. Then 50 mg of lipase from Candida cylindreacea (Lipase OF-360, Meito-Sangyo) was added to the solution and the mixture was stirred a 55 C for 24 h. The modified pectin was precipitated in methanol and recovered by filtration. After being washed extensively with methanol, the product was obtained as a powder. The yield was 0.98 g. Analysis of the product (MW 125,000, MW Mn 6.8) by size-exclusion chromatography indicated...

A LOS Biosynthesis in N meningitidis and N gonorrhoeae A Case Study

The pathogens Neisseria gonorrhoeae and Neisseria meningitidis have received much attention in the last few years. Neisserial lipo-oligosaccharide (LOS) is distinct from the LPS of the enteric gram-negative bacilli. The differences include phosphorylation patterns, composition and attachment of acyl chains, and the lack of the repeating O-antigen characteristic of the enteric species. In Neisseria species, the core region consists of Hep2-Kdo2 unit that is further elaborated with...

Pectin Glycerol Ester

Pectin is extracted from citrus peel, apple pomace, sugar beet, and other plant materials. Structurally it comprises polygalacturonic acid and its methyl ester, and a number of neutral sugars 15 . It is widely used in food applications (e.g., jams and jellies, confectionery, beverages, desserts) and in some pharmaceutical applications. It is susceptible to enzyme reactions, and the following three pectolytic enzymes are well known polygalacturonase (cleaving the galacturonan backbone), pectin...

Receptor Specific Glycopolymers for Bacteria Targeting

Antibody-based immunotherapy is often limited by a weak immunogenetic response. The complexity associated with the development of humanized antibodies has hindered progress for immunosuppressive therapy. Recently the direct use of human natural antibodies such as anti-Gal for the specific deletion of targeted bacterial cells has become very attractive 139,140 . The feasibility of using antibody targeting Figure 17 Energy grid map of a(1-3) linkage in trisaccharide 2. Isoenergy contours are...

Amphiphilic Calix[4arene Nanostructures

Guided by the need to prepare well-defined clusters having good binding properties in solid phase enzyme immunosorbent assays (ELISA) while having readily exposed carbohydrate ligands, we became interested in synthesizing glycosylated calix ra arene derivatives. In many ways, glycocalix ra arenes, which possess guest-host capabilities that can be used as drug vectors, are structurally related to cyclodextrins. Additionally, they have advantages unsurpassed by the cyclodextrins because they can...

Amplified Binding Differentiation of antiGal Isotypes by gal Polymers

The existence of differentiating anti-Gal antibody isotypes has allowed so-called isotype switching, a distinct process of recognition for antigen-antibody complex-ation 160 . Recent studies involving newborn baboons heterotropically transplanted with baby pig hearts have elucidated the isotype switch effect. The porcine hearts were rejected 4-6 days posttransplantation 161 . Six days postrejection of the graft, distinct anti-Gal IgM and IgG antibodies were detected. After an additional week,...

Strategy 1 Synthesis of Maidong Saponin C

Amphotericin Binding

Maidong, one of the most commonly used Chinese herbs, is held to nourish ''yin'' (tonic effect yin is one of the basic philosophical concepts in traditional Chinese medicine). Saponins are believed to be the active principles in Maidong plants, which are found in several species, including some in the Ophiopogon and Liriope genera. Thus far more than 60 steroidal saponins have been isolated from these species 2c . Yu et al. isolated Maidong saponin C (16) from the tuber of Liriope muscari 12 ....

Using Novel Active Latent Glycosylation Strategy to Produce Sialyloligosaccharides

Iodonium Dicollidine Perchlorate

The biological significance of V-acetylneuraminic acid containing oligosaccharides has stimulated remarkable progress in devising glycosylation strategies 36 . However, efficient protocols for building sialylated oligosaccharides from monosaccharide components is still a major challenge. Initially, acetochloroneuraminic acid (5) has been the glycosyl donor most widely used for the synthesis of a-sialosides, but its efficacy necessitates the use of a temporarily incorporated participating group...

Low Molecular Weight Trimeric Galactose Displays Can Be Potent Ligands for the Hepatic Lectin on the Cell Surface

Multivalent displays of galactose and -acetylgalactosamine epitopes have been synthesized to identify the features important for glycoconjugate recognition and en-docytosis by the hepatic lectin 117,118 . Initial studies, performed with galactose-substituted neoglycoproteins and polyacrylamide gels, demonstrated that the receptor binds more efficiently to multivalent ligands 119 . Since many natural saccharides contain branched or multiantennary structures, several groups postulated that...

C

Cmp Neuac Sialyltransferase

Wanted reaction pathways and the need for tedious protecting group schemes or stereocontrolling auxiliaries. In addition, sialyltransferases have been shown to tolerate several acceptor modifications 33 , although less is known about their donor specificity because the requisite CMP-NeuAc sugar donors are so difficult to Kinetic isotope effect studies with a particular transferase, namely, rat liver a-2,6-sialyltransferase, have shown that there is significant charge buildup at the an-omeric...

Cholesterol Lowering Conjugates Designed to Function Through the Hepatic Lectin

In contrast to the approaches described above in which molecules designed to function within the liver are delivered through their interaction with the hepatic lectin, a strategy to use the hepatic lectin to eliminate unwanted species from serum has also been investigated. Specifically, Biessen et al. attempted to take advantage of hepatic lectin mediated endocytosis and subsequent ligand proteolysis to lower serum cholesterol levels 134 . It was anticipated that targeting the proteins...

Product Isolation

For hydrophobic products like glycolipids or other aliphatic aglycones, C18 reversed phase supports can be used for their isolation from enzyme reactions. In milligram-scale synthesis, C18 Sep-Pak cartridges from Waters perform well. The resin or cartridge should be preconditioned before use by washing with MeOH, then equilibrated with water before aqueous enzymatic reaction samples are loaded. Organic solvents such as glycerol or DMSO in enzymatic reactions prevent substrates from binding to...

H

Glycosyl Amino Acids

With DBU in acetonitrile to afford the product of elimination 21 in good yield (Scheme 5). The same chemistry was carried out on the d-manno and d-galacto derivatives which gave the analogous compounds in similar yields 9 . Work by Magnusson dealt with the application of allylic sulfones as radical acceptors for allylic carbon-carbon bond formation at the radical center. Various acceptors were utilized, and the products are shown in Scheme 6 10 . The Kolbe electrolysis of sugar acids to give...

Hn

4-Guanidino-Neu5Ac2en (3) (GG167, Ki 0.1 nM) Unfortunately, medicinal applications of carbohydrate binding protein inhibitors suffer from major drawbacks. Except for a few marginal cases, carbohydrates show deceptively low binding affinities toward their receptor counterparts 7 . Moreover, simple or more complex oligosaccharides are poorly bioavailable and are rapidly catabolized through various glycosidases. A few strategies are being pursued to overcome these difficulties. Among these, the...

Introduction

The chemistry of C-glycoside compounds has been of considerable interest over the last 20 years. This class of compounds is defined as compounds in which the exo-cyclic oxygen atom of an O-glycoside has been replaced by a carbon atom (Fig. 1). C-Glycosides are not solely man-made, but are the creation of nature, as attested by the occurrence of many C-glycoside natural products. Unlike the corresponding O-glycosides, C-glycosides are unaffected by hydrolytic or enzymatic cleavage and therefore...

Naturally Occurring Pyranosyl Sugar Amino Acids

Glycopeptides are a large class of naturally occurring molecules containing a carbohydrate glycosidically linked to an a-amino acid, which is typically a component of a peptide or protein. There are both N- and O-linked glycopeptides. N-Acetylga-lactosamine linked a to serine is the major O-glycosidic linkage, whereas N-acetyl-glucosamine linked to asparaginine characterizes N-linked glycopeptides (Fig. 1) 1 . Sugar amino acids are carbohydrates containing both amine and carboxylic acid...

Prototypical Glycoconjugates On Cell Surfaces

Cell surface glycoconjugates can be grouped into four main classes N-linked glycoproteins, O-linked glycoproteins, glycosyl phosphatidylinositol (GPI)-anchored proteins, and glycolipids. These are the major cell surface hosts of monosaccharides derived from intracellular metabolism. N-Linked glycosylation in eukaryotes is a cotranslational event that occurs in the endoplasmic reticulum (ER) 2,16 . It is found almost exclusively on proteins that contain the consensus sequence AsnXaaSer Thr...

Overview Of Metabolic Substrate Engineering

Biochemistry Common Core Oligosaccharide

The complex glycoconjugates expressed on eukaryotic cell surfaces (Figs. 3-8) comprise primarily 10 monosaccharides Glc, Gal, Man, Fuc, GlcN, GlcNAc, GalNAc, Xyl, GlcUA, and sialic acid (Neu5Ac). These sugars can be biosynthesized de novo within a cell, often from Glc or, in many cases, key metabolic intermediates can be supplied exogenously to a cell. The pathways for these interconversions are summarized in Figure 9 33-36 . If the enzymes in these biosynthetic pathways could tolerate...

Summary

Saponins are distributed widely in plants, including many significant foodstuffs and medicinal plants. In traditional Chinese herbal medicine, saponin components are of special importance many of them exhibit various interesting bioactivities. However, research on saponins has been limited to the isolation of these compounds and the determination of their structure. Pharmacological evaluation of saponins has been mainly retained at the folkloric level. The difficulty in isolation of saponins...

Iipolysaccharides And Product Development

Figure 1 gives a simplified product development scheme. The raw material may come from seeds (e.g., guar, locust bean gum, corn, wheat starch), tubers and roots (e.g., potato and tapioca starch, konjac), fruits (pectin), seaweeds (e.g., agar, alginate, car-rageenan, furcellaran), plant exudates (e.g., ghatti, gum arabic, karaya, tragacanth), and various plant sources (cellulose), or microorganisms (dextran, gellan, pullulan, xanthan). These substances are collected through appropriate means,...

Coupling Via Glycosyl Oxophosphonium Intermediates

Glycosyl Amino Acids

The in situ generation of glycosyl oxophosphonium salts has been shown to be useful for one-pot couplings with 1-hydroxy glycosyl donors. The most common method employed for the generation of the carbohydrate oxophosphonium intermediates 35 occurs by way of the Mitsunobu protocol 25 or variants thereof (Scheme 9). The method typically employs the initial reaction of a dialkyl azodicarboxylate with a phosphine substrate in the presence of a weak acid to generate a quaternary phos-phonium salt,...

Glycopolymers

We introduced the term glycopolymer to identify water-soluble polymers onto which carbohydrate haptens are covalently appended 72 . In this respect, glycopoly-mers should differ from pseudopolysaccharides, which refer to chemically modified polysaccharides and to insoluble materials used in affinity chromatography. Curiously, we initially made the first sialylated glycopolymers 73 to screen anti-sialic acid antibodies obtained from a sialylated neoglycoproteins 18b,73-75 . The original aim was...

Oh

Years before an aggressive exploration of this rich field of chemistry began. The art that followed the pioneering work of Yoshimura, Fuchs, and Lehmann can be classified into two categories (1) syntheses involving mixed congeners, having either self-terminating residues and or a combination of sugar amino and a-amino acids, and (2) homo-oligomeric syntheses composed of one sugar amino acid joined in consecutive amido linkages. A. Syntheses of Mixed Sugar Amino Acid Conjugates In 1994 Kessler...

References

Glycobiology 1993, 3, 97. (b) Varki, A. FASEB J. 1997, 248. (c) Schauer, R. Kamerling, J. P. In Glycoproteins II, Montreuil, J., Vliegenhart, J. F. G., Schachter, H., eds. Elsevier Amsterdam, 1997, pp. 243-402. 2. (a) Okamoto, K Goto, T. Tetrahedron 1990, 46, 5835. (b) DeNinno, M. Synthesis 1991, 583. (c) Hasegawa, A. Kiso, M. In Carbohydrates Synthetic Methods and Applications in Medicinal Chemistry, Ogura, H., Hasegawa, A., Suami, T., eds. VCH New York, 1992, pp. 243-266. 3. (a)...

Spacing and Orientation of the Saccharide Epitopes Is Important for ConA Interaction

Low molecular weight divalent and trivalent ligands have also been generated to probe ConA ligand recognition. As had been shown with the hepatic lectin (see Section V.C) 96,97 and influenza virus hemagglutinin (see Sections VI.E-VI.F) 98 , low molecular weight ligands can achieve high potencies, displaying inhibitory potencies 100- to 1000-fold higher than those of the corresponding monovalent saccharides. To investigate the effect of epitope spacing and orientation in ConA binding, Roy and...

Specificity in Multivalent Recognition Concanavalin A Discriminates Between Related Multidentate Ligands

The specificity of ligand binding for a multivalent protein-carbohydrate interaction was explored by using ConA. ConA binds both glucose and mannose residues, but it binds monovalent C-mannoside 9 with a slightly (0.2 kcal mol) more favorable free energy than the corresponding C-glucoside 8 (Fig. 12) 54 . Whether the small difference observed in the monovalent binding event would be manifested with the corresponding multivalent ligands has been explored. By examining the ability of glucose- and...

Conclusion

Carbohydrate research has lagged behind work done on the other two well-known macromolecules, proteins and nucleic acids. This was mostly due to the enormous variety and complexity of oligo polysaccharide structures found in nature. With the discovery of the multiplicity of roles now assigned to carbohydrate molecules, there is an increasing need for methodologies that will allow researchers access to these structures. Organic synthetic methods are available for the production of...

Sites Of Rnaaminoglycoside Interactions

Aminoglycoside antibiotics, as discussed in the preceding section, interact with RNA. Ribosome is the target for this class 10-12,148 , and the antibiotics exert their antibacterial effects by binding to ribosomal RNA (rRNA) in the A site, causing misreading of the genetic code and inhibiting the process of translocation 149,150 (see above). Aminoglycoside antibiotics also interact with a variety of other biologically relevant RNA molecules. These include mRNA from human immunodeficiency virus...

Syntheses And Structural Characterization Of Amidolinked Oligomers With Stable Secondary Structure

Although this chapter is focused on carbohydrate-based compounds, it is important to briefly describe the pioneering work of Gellman and Seebach directed to the syntheses of amido-linked oligomers derived from - and y-amino acids that are not based on carbohydrates. These researchers and others 55 have engineered systems that adopt stable helical, sheet, and turn conformations in solution. Surprisingly, in many cases as few as four residues is sufficient to stabilize the conformation. This...

Conformational Studies

A detailed appreciation of the biological function of a molecule requires that its conformation be understood. Therefore, in recent years a great deal of effort has been directed toward elucidating the solution conformation of oligosaccharides 92 . The work, however, has been heavily focused on oligopyranosides. At the same time, a wealth of information detailing the conformation of furanose rings in nucleotides and nucleic acids has accumulated 93 . However, except for sucrose 94,95 , only...

Multivalent Saccharide Display on Beads Alters the Ligand Preference

Bauhinia Purpurea Side Effects

The role of ligand presentation in affinity is also highlighted by the fact that functional affinity trends observed with monovalent ligands do not necessarily mirror the effects observed when these ligands are assembled into multivalent displays. Seeking to identify highly active monovalent ligands, Kahne and colleagues developed a combinatorial synthesis yielding a library of disaccharide ligands on TentaGel beads 38 . A mixed population of the beads was assayed for activity against...

Using Sialyltransferases For The Synthesis Of Sialosides

Enzyme-mediated glycosylations are powerful methods for the synthesis of complex carbohydrates, including those that contain sialic acid 30,31 . In mammalian systems, Leloir pathway glycosyltransferases are responsible for the biosynthesis of most glycoconjugates 32 . Sialyltransferases are a subset of the glycosyltransferases that transfer the NeuAc component of acid (88, CMP-NeuAc) to acceptor hydroxyl groups with inversion of configuration at the anomeric center (Scheme 28) 30,31 ....

Syntheses of Suitably Functionalized Sialosides

It is clear that multivalent sialosides may offer numerous opportunities for ''medicinal glycobiology.'' They can be used to increase receptor binding interactions in areas such as flu virus inhibition of hemagglutination, anti-inflammatory agents (se-lectin antagonists), cancer vaccines and immunodiagnostics, and in treating gastrointestinal infections. Moreover, inasmuch as sialic acid receptor themselves might be organized as clusters, it appeared sound to synthesize multivalent glycoforms...

Structural Features And Energetics

A number of specific components contribute to the complex energetics of lectin-ligand interactions. The observed affinities (functional affinities, see Section II.B.1) for these processes arise from the features of the monovalent and multivalent binding interactions. As a prelude to an examination of specific multidentate interactions, this section describes the features of monovalent protein-saccharide complexation and the factors that contribute to the high functional affinities observed for...

Methodologies in Syntheses of Aminoglycoside Antibiotics

Aminoglycoside Antibiotics

Jalal Haddad, Mei-Zheng Liu, and Shahriar Mobashery Wayne State University, Detroit, Michigan Many aminoglycoside antibiotics that are being used as therapeutic agents are semisynthetic products. These compounds show excellent antibiotic properties, yet they suffer from ototoxicity and renal toxicity. Furthermore, bacterial resistance to aminoglycosides is widespread among pathogens, resulting in failure of these antibiotics in the treatment of infectious diseases. As a consequence, these...

Preface

Ever since Emil Fischer established the stereochemical configuration of d- -glu-cose at the end of the nineteenth century, carbohydrate chemistry has become an important branch of organic chemistry. Steady advances in carbohydrate synthetic and analytical methods have been made over the past hundred years. However, it is the past two decades that have seen remarkable new discoveries in the biology of carbohydrates and provided renewed impetus to the synthesis of complex glycocon-jugates and...

Overview of the Glycal Assembly Approach

While the donor-bound paradigm Case 2 minimizes the number of protecting group manipulations that have to be carried out on the solid support, it mandates the presence of a latent glycosyl donor moiety in the solution-based glycosyl acceptor. Glycal building blocks fulfill these requirements, since they serve as glycosyl acceptors but may be converted into powerful glycosylating agents. Danishefsky and coworkers successfully explored the application of the glycal assembly method to the solid...

Strategy 1 Synthesis of OSW1

Benzyl Penicillin

Saponin OSW-1 1 is the major component of a small group of cholestane saponins isolated by Sashida et al. from the bulbs of Ornithogalum saudersia. This molecule, while showing little toxicity to normal cells in vitro, exhibited remarkable activities against a broad spectrum of malignant tumor cells, with IC50 between 0.1 and 0.7 nM, which is about 10-100 times more potent than such clinical anticancer agents as mitomycin C, adriamycin, cisplatin, camptothecin, and taxol 9 . According to...

Fisher Glycosylation

Furanose glycosides of simple alcohols are conveniently obtained by subjecting a reducing sugar to a controlled Fisher glycosylation reaction. The furanosides are the kinetic products of this reaction, and excellent yields of the product as a mixture of anomers are usually obtained if the proper conditions are chosen 67 . The alcohol generally used in this reaction is methanol, which serves as both a reactant and the solvent. The methyl glycosides thus obtained must then be protected and...