Current Topics in Medicinal Chemistry

ISSN: 1568-0266

Current Topics in Medicinal Chemistry
Volume 8, Number 2, 2008

Contents

New Directions in the Chemistry and Biology of Carbohydrates
Guest Editor: Robert M. Giuliano


Editorial Pp. 63


Synthetic TLR4-Active Glycolipids as Vaccine Adjuvants and Stand-Alone Immunotherapeutics Pp. 64-79
David A. Johnson
[Abstract] [Purchase Article]


Immobilization of Heparin: Approaches and Applications Pp. 80-100
Saravanababu Murugesan, Jin Xie and Robert J. Linhardt
[Abstract] [Purchase Article]


Pyranose N-Glycosyl Amines: Emerging Targets with Diverse Biological Potential Pp. 101-113
Peter Norris
[Abstract] [Purchase Article]


The De Novo Synthesis of Oligosaccharides: Application to the Medicinal Chemistry SAR-Study of Digitoxin Pp.114-125
Maoquan Zhou and George O’Doherty
[Abstract] [Purchase Article]


Recent Developments in Synthetic Oligosaccharide-Based Bacterial Vaccines Pp. 126-140
Vince Pozsgay
[Abstract] [Purchase Article]


Current Understanding on Biosynthesis of Microbial Polysaccharides Pp. 141-151
Hongjie Guo, Wen Yi, Jing K. Song and Peng George Wang
[Abstract] [Purchase Article]


High-energy Glycoconjugates: Synthetic Transformations of Carbohydrates Using Microwave and Ultrasonic Energy Pp. 152-158
Eugene A. Cioffi
[Abstract] [Purchase Article]


Carbohydrate-Based Drugs in the Treatment of Epilepsy, Depression and Other Affective Disorders Pp. 159-170
Ian Jamie Talisman and Cecilia H. Marzabadi
[Abstract] [Purchase Article]


Molecule of Month Pp. 171



Abstracts

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Editorial

The idea for this special issue of Current Topics in Medicinal Chemistry was generated during a Gordon Research Conference on Carbohydrates that I attended in 2005. Having attended several of these conferences over the past 25 years, I was struck by the growth in our understanding of the chemistry and biology of carbohydrates, and the possibilities that now exist for the application of that understanding to the development of new therapies in medicine. It seemed an appropriate time to bring wider exposure of the advances in carbohydrate science to the medicinal chemistry community.

The important role that cell-surface carbohydrates play in biological interactions has come to be widely appreciated as tools have been developed for the chemical synthesis and study of carbohydrate-protein and carbohydrate-lipid conjugates. Glycoconjugates on the surface of a cell provide receptors for cell-cell recognition at the molecular level, and are involved in such processes as the regulation of cell growth and repair, cell adhesion and migration, and in pathological conditions such as tumor metastasis in cancer. Our recognition of the roles that carbohydrates play in these processes will continue to inspire research in the field of synthetic vaccines, a topic that is featured in several of the articles in this issue. The use of synthetic vaccines incorporating oligosaccharides holds promise in the treatment of bacterial infections, and also in the treatment of AIDS and cancer. Understanding the biosynthesis of cell-surface oligosaccharides is also important to the identification of potential targets for pathogenic organisms, and the use of vaccine adjuvants has been expanded to include carbohydrate mimetics of lipid A that interact with toll-like receptors. The anticoagulant heparin, a glycosaminoglycan, is one of the most widely prescribed medications in the world. The pharmacokinetics and pharmacodynamics of heparin may be improved through the use of immobilized heparins, which also have potential for applications in regulating other biological pathways.

Carbohydrate-based drugs are finding new applications in the treatment of CNS disorders, and pyranose N-glycosyl amines have been found to have a range of interesting biological activities and potential in the treatment of infection and inflammation. New synthetic methodology will always find important applications in the development of carbohydrate-based drugs of the complexity found in this issue. A review on the use of ultrasound and microwaves in carbohydrate chemistry and one on palladium-catalyzed glycosylation describe advances in carbohydrate synthesis by these methods. Our ability to synthesis complex, carbohydrate-derived therapeutic agents, coupled with our increased understanding of the roles of glycoconjugates in biology will hopefully lead to promising treatments for a wide range of diseases.


Robert M. Giuliano
Professor
Department of Chemistry
Villanova University
Villanova, PA 19087
robert.giuliano@villanova.edu


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Synthetic TLR4-Active Glycolipids as Vaccine Adjuvants and Stand-Alone Immunotherapeutics
David A. Johnson

The design of vaccine adjuvants and stand-alone immunotherapeutics has historically been a mix of alchemy and accident partly because of the complex nature of the molecular mechanisms involved in immune system function. The recent discovery of pattern recognition receptors and toll-like receptors (TLRs) in particular on cells of the immune system has shown the important role that stimulation of these cell receptors by microbial products plays in both innate and adaptive immune responses. Considerable effort has been directed at developing pharmaceutically acceptable mimetics of many TLR-active natural products, including the main cell-surface component of Gram-negative bacteria: lipopolysaccharide (LPS). LPS and its active principle, lipid A, are potent stimulators of host defense systems via their interaction with TLR4. However, the profound pyrogenicity and lethal toxicity of LPS and lipid A have precluded their medicinal use. Structure/activity investigations on natural S. minnesota R595 lipid A and its derivatives have led to the development of a novel class of synthetic lipid A mimetics known as aminoalkyl glucosaminide phosphates (AGPs). This review discusses the evolution of the AGPs and related TLR4-active glycolipids with emphasis on structure/activity relationships in the AGP series and pre-clinical/clinical development of selected AGPs, including the potent vaccine adjuvant RC-529.


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Immobilization of Heparin: Approaches and Applications
Saravanababu Murugesan, Jin Xie and Robert J. Linhardt

Heparin, an anticoagulant, has been used in many forms to treat various diseases. These forms include soluble heparin and heparin immobilized to supporting matrices by physical adsorption, by covalent chemical methods and by photochemical attachment. These immobilization methods often require the use of spacers or linkers. This review examines and compares various techniques that have been used for the immobilization of heparin as well as applications of these immobilized heparins. In the applications reviewed, immobilized heparin is compared with soluble heparin for efficient and versatile use in each of the various applications.


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Pyranose N-Glycosyl Amines: Emerging Targets with Diverse Biological Potential
Peter Norris

Interest in the chemistry and biological properties of non-nucleoside N-glycosidic compounds has gathered pace over the past several years; the occurrence of the N-glycoside moiety in glycoproteins and a range of active natural products has prompted the synthesis of a diverse spectrum of related materials with promising potential in medicinal chemistry. Particularly prominent has been the synthesis of novel N-glycosyl amides, 1,2,3-triazoles, and progress in the construction and diversification of natural products such as the mannopeptimycins and indolocarbazoles, each of which are discussed in this article.


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The De Novo Synthesis of Oligosaccharides: Application to the Medicinal Chemistry SAR-Study of Digitoxin
Maoquan Zhou and George O’Doherty

To address the medicinal chemist’s need for new synthetic methods for the preparation of unnatural carbohydrates, a new de novo method for carbohydrate synthesis has been developed. These routes use a palladium catalyzed glycosylation reaction to stereoselectively control the anomeric center and subsequent diastereoselective post glycosylation to install the remaining sugar stereocenters. The utility of this method was demonstrated by the syntheses and biological evaluation of several digitoxin oligosaccharide analogues.


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Recent Developments in Synthetic Oligosaccharide-Based Bacterial Vaccines
Vince Pozsgay

Synthetic advances made possible chemical assembly of complex oligosaccharide fragments of polysaccharide domains on the surface of human pathogenic bacteria. These oligosaccharides may be recognized by antibodies raised against high molecular weight, native, polysaccharides. In addition to their antigenicity, synthetic oligosaccharides can also function as haptens in their protein conjugates that can elicit not only oligo- but also polysaccharide-specific IgG antibodies in animal models and in humans. A major milestone in the development of new generation vaccines was the demonstration that protein conjugates of synthetic fragments of the capsular polysaccharide of Haemophilus influenzae type b are as efficacious in preventing childhood meningitis and other diseases as is the corresponding licensed commercial vaccine containing the bacterial polysaccharide. The lessons learnt in this and other endeavors described herein are manifold. For example, they teach us about the significance of the oligosaccharide epitope size, the number of their copies per protein in the conjugate, the possible effect of the spacer on anti-saccharide immune response, and the proper choice of the carrier protein combined with the selection of the animal model. The H. influenzae b story also teaches us that that the synthetic approach can be commercially viable.


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Current Understanding on Biosynthesis of Microbial Polysaccharides
Hongjie Guo, Wen Yi, Jing K. Song and Peng George Wang

The surfaces of almost all microbes are decorated with remarkable variations of polysaccharides such as O-antigen, capsular polysaccharides (CPS), and exopolysaccharides (EPS) in bacteria, lipoarabinomannans (LAM) in mycobacteria and lipophosphoglycan (LPG) in Leishmania. These polysaccharides play important roles in many biological processes, and they can function as the virulence determinants in the pathogens. The basic structures of these polysaccharides are known, but they show species-specificity or stage-specificity. For example, there are 186 O-serotypes and 80 capsular serotypes in E. coli. Despite the variation, the range of strategies used for the biosynthesis and assembly of these microbial polysaccharides is limited. Depending on the assembly and translocation mechanisms, O-antigen biosynthesis is subdivided into three pathways, of which the Wzy-dependent pathway is widely used not only in O-antigen, but also in CPS and EPS.


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High-energy Glycoconjugates: Synthetic Transformations of Carbohydrates Using Microwave and Ultrasonic Energy
Eugene A. Cioffi

Methods to transform carbohydrates are often complex and tedious, both due to the vast array of naturally occurring and synthetically designed scaffolds which may manifest meager to drastic reactivity, dependent upon the transformation sought and the stereogenic site chosen. In order to facilitate and expedite desired synthetic transformation, many researchers are utililizing microwave and ultrasonic irradiation to achieve their goals, in generally high yields within a shorter period of time, and often without undesirous byproducts. The basic physical principles underlying the energy regimes are qualitatively discussed prior to review of the applications in carbohydrate syntheses and transformation. This literature review looks at research involving glycosylations, -OH group conversions, isotopic incorporation, and C-N bond formation. Instances of improved yields and selectivities resultant from the use of these high-energy sources will be highlighted.


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Carbohydrate-Based Drugs in the Treatment of Epilepsy, Depression and Other Affective Disorders
Ian Jamie Talisman and Cecilia H. Marzabadi

Mental illness affects a quarter of the US population. Recently, it has been shown that new, carbohydrate-based drugs hold promise in the treatment of central nervous system (CNS) disorders. A variety of ways in which drugs of this sort may reduce the symptoms of epilepsy, depression and other affective disorders have been proposed, including: targeting the immune system, disrupting glycolysis, acting at different sites in the hypothalamic-pituitary-adrenal (HPA) axis, and targeting specific biochemical pathways such as the inositol pathway. In the present review, the structureactivity relationships (SARs) of a wide variety of CNS-active carbohydrates are presented.