Current Topics in Medicinal Chemistry - Volume 5, Issue 14, 2005

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.

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 OC rearrangement, umpolung, and miscellaneous reactions.

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.

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.

This paper reviews the recent advances in the synthesis of catabolically stable sugar mimetics, Coligosaccharides. 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.

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 exoglycals as the starting materials. The target molecules can be categorized into three groups, namely C-glycosides, enzyme inhibitors and bioactive natural products.