Current Topics in Medicinal Chemistry

ISSN: 1568-0266

Current Topics in Medicinal Chemistry
Volume 5, Number 14, 2005

Contents

C-Glycosides and Related Sugar Derivatives in Medicinal Chemistry
Guest Editor: Wei Zou


Editorial Pp.1297


Bioactive C-Glycosides from Bacterial Secondary Metabolism Pp.1299
Philip G. Hultin
[Abstract]


Recent Advances in Aryl C-Glycoside Synthesis Pp.1333
David Y. W. Lee and Minsheng He
[Abstract]


Recent Advances in the Synthesis of C-linked Glycoconjugates Pp.1351
Elisabeth von Moos and Robert N. Ben
[Abstract]


C-Glycosides and Aza-C-Glycosides as Potential Glycosidase and Glycosyltransferase Inhibitors Pp.1363
Wei Zou
[Abstract]


Recent Advances in the Synthesis of C-Oligosaccharides Pp.1393
Xuejun Yuan and Robert J. Linhardt
[Abstract]


exo-Glycal Chemistry: General Aspects and Synthetic Applications for Biochemical Use Pp.1431
Chun-Hung Lin Hui-Chang Lin and Wen-Bin Yang
[Abstract]




Abstracts

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Editorial

C-Glycosides and Related Sugar Derivatives in Medicinal Chemistry
Glycosylated natural products are widely present in microorganisms and plants as secondary metabolites. Traditionally, the carbohydrate moieties in these molecules are thought to play a limited role in the control of drug pharmacokinetics. However, recent evidence regarding carbohydrate-RNA/DNA and carbohydrate-protein interactions suggests that the carbohydrate moieties are vital to their bioactivities.

In fact, over half of the world’s drug leads derive directly from natural products and many of them are glycosylated, including C-glycoside antibiotics and enzyme inhibitors. Obviously, as a part of drug development, the research in this area deserves special attention in medicinal chemistry.

This issue of Current Topics in Medicinal Chemistry, dedicated to C-glycosides and related sugar derivatives, contains reviews on the current status and future directions in this ever-expanding field. These reviews are organized with the intention to present readers with a wide scope of topics, from C-glycoside natural products to synthetic C-glycosides and C-oligosaccharides with particular emphasis on the synthetic methodologies.

The opening review by P. Hultin introduces the bioactive C-glycosides produced by bacterial secondary metabolism. Although C-glycosides have been isolated from various bacteria, the review focuses particularly on the C-glycosides from Streptomyces. An overview on these C-glycosides including their biosynthetic pathway, structure diversity, and bioactivities was put forward comprehensively with historical perspectives. Examples were also given on the enzymatic C-glycosylation by C-glycosyltransferases. This sets the stage nicely for the following review.

A growing number of glycosylated secondary metabolites, some of which are under clinical development, are found to be aryl C-glycosides. Although these C-glycosides are synthesized in nature by C-glycosyltransferases, the scaled biosynthesis hasn’t become practical due to the lack of purified enzymes. The major thrust toward aryl C-glycosides has been the chemical synthesis, which is the subject of the review by D. Lee and M. He. Besides an overview of the chemistry used to construct bioactive aryl C-glycosides, interestingly, they have also outlined a new potential application of aryl C-glycosides, i.e. treatment of heavy alcohol drinking.

With a greater understanding of protein glycosylation and its implication to various biological functions or malfunctions, glycoproteins have been considered therapeutic targets. In comparison to O- and N-linked glycoconjugates, C-glycoconjugates can resist chemical and enzymatic degradation and may have better pharmacokinetic properties. A review by E. von Moos and R. Ben brought us the new synthetic methodologies for C-glycopeptides developed in the last few years.

One of the most anticipated medicinal applications from glycosciences is using small molecules as specific inhibitors of glycoprocessing enzymes (glycosidases and glycosyltransferases) to treat diseases such as diabetes, viral infections, cancers and other glyco-deficiencies. Notable success has been achieved in the last decade, as evidenced by the regulatory approval of five drugs. The second generation of such inhibitor drugs must exhibit improved specificity and better bioavailability. A review by myself summarized the current developments in the area and specifically focused on the aza- C-glycosides because it is believed that the required specificity of enzyme inhibition and the bioavailability can be met though fine-tuning of the aglycon structures.

In comparison to O-oligosaccharide synthesis, which has taken the center stage of carbohydrate chemistry over the last century, chemical synthesis of C-oligosaccharides is a new developing area. Although there is no immediate medicinal application on the horizon, C-oligosaccharides are useful tools in glycosciences for the enzyme mechanistic and conformational studies. Recent advances in the synthesis of C-oligosaccharides are reviewed by X. Yuan and R. J. Linhardt, which provide a comprehensive update on the methodologies available in that regard. The C-linked oligosaccharide analogs of natural products may become the next synthetic targets that offer more favorable pharmacological properties.

As versatile intermediates to C-glycosides and other bioactive natural products, exo-glycals have attracted considerable attention. The review by C.-H. Lin, H.-C. Lin and W.-B. Yang describes the development of both exo-glycal preparation and further stereoselective functionization. The examples of exo-glycal derived biologically important molecules, including antitumor agents and enzyme inhibitors, demonstrated the possibility of even wider medicinal applications in the future.

Unfortunately, this issue of Current Topics in Medicinal Chemistry does not include two important emerging areas related to C-glycosides. One is the role played by C-glycoconjugates in immune response and the other is on the synthesis of diverse C-glycosylated metabolites through genetic engineering of C-glycosyltransferases. I believe both will make immense contribution to the advancement of glycosciences, which will certainly benefit medicinal chemistry.


Wei Zou, Ph.D.
Institute for Biological Sciences
National Research Council of Canada
Ottawa, Ontario, Canada K1A 0R6


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Bioactive C-Glycosides from Bacterial Secondary Metabolism
Philip G. Hultin

C-Glycosides are commonly regarded as unusual structures, but they are far more prevalent among natural products than is imagined. This review discusses the C-glycosidic compounds produced by various bacteria, particularly the “biosynthetically talented” Streptomyces. The major structure types are presented, along with brief descriptions of the known biological and pharmacological properties of the compounds. Recent work has uncovered the genetic basis for the biosynthesis of several bacterial C-glycosides, and emphasis is placed on those cases where it has been possible to identify (at least provisionally) the C-glycosyltransferase in the pathway. Prospects for biosynthetic engineering, combinatorial biosynthesis, or glycorandomization in C-glycosidic natural products are briefly discussed.


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Recent Advances in Aryl C-Glycoside Synthesis
David Y. W. Lee and Minsheng He

Aryl C-glycosides are stable analogs of the corresponding O-glycosides. Because of their favorable pharmacological profiles attributed primarily to the C-glycosyl moiety, aryl C-glycosides have gained increasing popularity as drug candidates. In this review we focus on the synthesis of aryl C-glycosides including puerarin and kendomycin. This review is organized based on the type of chemistry used in the assembly of the C-glycosides with the following sub-sections: electrophilic reaction, cross-coupling reaction, free radical reaction, cyclization, intramolecular O-C rearrangement, umpolung, and miscellaneous reactions.


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Recent Advances in the Synthesis of C-linked Glycoconjugates
Elisabeth von Moos and Robert N. Ben

During the last five years, the scientific community has seen a dramatic increase in the number of synthetic methods or strategies to prepare C-linked glycoconjugates. One reason for this increase is that the biological significance and roles of many O- and N-linked glyconconjugates has become evident. This review will summarize the biological importance of glycoconjugates and outline recent advances in the preparation of C-linked glycoconjugates that have appeared in the literature since the new millennium.


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C-Glycosides and Aza-C-Glycosides as Potential Glycosidase and Glycosyltransferase Inhibitors
Wei Zou

Glycosylation as one of most important post-translational modification of gene products is often critical to specific cellular biological functions. Since elevated glycoprocessing enzyme activities have been implicated in the development of various diseases including cancer metastasis, glycosidases and glycosyltransferases are considered as therapeutic targets. Azasugars, the first generation of enzyme inhibitors, have been extensively investigated and two azasugar-based drugs (Miglitol and Miglustat) have been approved. Aza-C-glycosides, molecules with an azasugar core and various C-aglycons attached at the pseudo anomeric center, have the potential to become the second-generation inhibitors with improved specificity and membrane permeability. In this review, C-glycosides, aza-C-glycosides, and aza-C-disaccharides are introduced as glycoprocessing enzyme inhibitors. The synthetic approaches toward those molecules are described based on the key reactions, which include reductive amination, nucleophilic ring opening of epoxides, nucleophilic addition to imines (C=N), and hetero-Michael additions. Aza-C-glycoside-based libraries are also described for the discovery of promising second-generation inhibitors.


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Recent Advances in the Synthesis of C-Oligosaccharides
Xuejun Yuan and Robert J. Linhardt

This paper reviews the recent advances in the synthesis of catabolically stable sugar mimetics, C-oligosaccharides. These compounds are synthetic analogs of the naturally occurring O-oligosaccharides, in which the interglycosidic oxygen has been replaced by a methylene group. This review is organized in terms of chemistry used to assemble C-oligosaccarides under the sub-headings: anionic approaches, cationic methods, reductive glycosyl samarium chemistry, cyclization methodology, and free radical chemistry.


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exo-Glycal Chemistry: General Aspects and Synthetic Applications for Biochemical Use
Chun-Hung Lin Hui-Chang Lin and Wen-Bin Yang

It is well known that carbohydrates play an indispensable role in a variety of essential biological activities, such as cell-cell adhesion, bacteria and virus infections, and tumor metastasis. Among an increasing number of sugars and sugar mimetics that have been designed and synthesized for the purpose of drug discovery, C-glycosides are considered to be one of the best choices on account of their stability and resemblance as they differ from normal glycosides only in glycosidic linkages. exo-Glycals are unsaturated sugars that have a double bond attached to the anomeric center outside the sugar ring. These carbohydrate molecules are useful for the synthesis of C-glycosides and compounds containing quaternary carbons, provided that the olefin can be properly reduced or functionalized. This review places special emphasis on two aspects of exo-glycals including general methods of preparation and synthetic applications for making biologically important molecules. The first half discusses the methods of addition/elimination and Ramburg-Bäcklund rearrangement that offer many beneficial features including a wide range of double bond substitutions, limited reaction steps, easy operation and good overall yields. The rest of the article demonstrates a number of synthetic studies using exo-glycals as the starting materials. The target molecules can be categorized into three groups, namely C-glycosides, enzyme inhibitors and bioactive natural products.