Glycosyl mimetics

In addition there is at least one area where enzyme-catalysed reactions have established themselves as the first line of attack for solving synthetic problems that area involves the transformations of carbohydrates. Indeed, biocatalysed transformations of saccharides is becoming increasingly popular and roughly 10% of the recent literature (Year 2000) on biotransformations involves the preparation and modification of carbohydrates. Early literature on chemoenzy-matic approaches for the synthesis of saccharides and mimetics has been reviewed by a pioneer in the field, C.-H. Wong[158]. For one of the most popular areas, enzyme-catalysed glycosylation reactions, a useful survey is also available, penned by the same senior author[159]. 

Andre, S. Pei, Z. Siebert, H.-C. Ramstrom, O. Cabins, H.-J. Glycosyl-disulfides from dynamic combinatorial libraries as O-glycoside mimetics for plant and endogenous lectins Their reactivities in solid-phase and cell assays and conformational analysis by molecular dynamics simulations. Bioorg. Med. Chem. 2006,14, 6314-6326. 

Due to the biological roles of glycolipids, many papers have been devoted to their syntheses over the last ten years. The coupling of a fully protected carbohydrate donor to a lipid acceptor requires efficient and highly stereoselective glycosylation methods because lipid derivatives often have low reactivity. A few examples of glycosphingolipids syntheses will be discussed below as well as multistep preparations of other amphiphilic carbohydrates designed as biochemical mimetics, surfactants or liquid crystals. 

Fig. 9. Substrate mimetics and chemoselectively N-glycosylation to the corresponding neoglyco-peptides as OT inhibitors.

Despite the small size of glycolipids, their complexity has still driven efforts for synthesis of simpler mimetics in an attempt to identify the minimal structural features required for the biological activity. To this end, many synthetic methods have been adopted in glycolipids synthesis, based on traditional glycosylation... 

A number of functional sialyl Lewis mimetics have been synthesized. Their activities in vitro are equal or even better than those of the tetrasac-charide itself. To overcome synthetic problems, efficient stereoselective glycosylations as well as new chemoenzymatic methods for C-C bond formations had to be developed. The substitution of neuraminic acid by (5)-phenyl- and (5)-cyclohexyl lactic acid, as less flexible glycol acid residues, turned out to be very successful [10]. Also, a phosphate and a sulfate group, respectively, mimic neuraminic acid without loss of activity [11]. (5)-Cyclohexyl lactic acid-mimetic 2 shows a more than ten-fold efficacy compared with sialyl Lewis, whereas the corresponding (/ )-isomer 3 is almost inactive [10]. The deviating orientation of the carboxylic acid functionality compared to the bioactive sialyl Lewis conformation leads to the examined loss of activity. It was shown by transfer-NOE measurements of the corresponding E-selectin complexes that the coordinates of the bioactive conformation of sialyl Lewis and of compound 2 are similar. Con.se-quently structure 2 should bind to E-selectin in the same manner as that of sialyl Lewis [ 10a, b]. 

Several 0-GlcNAcase inhibitors have been described, the most popular are streptozotocin (STZ) and PUGNAc. Both of these compounds are substrate mimetics that inhibit 0-GlcNAcase activity by resembling the natural substrate s ox-azoline transition state after its entrance into the active site (50, 51). Unfortunately, the above inhibitors are nonselective and can inhibit other glycosyl hydrolases therefore, they are a detriment to a multitude of cell pathways. Another, more potent transition state analog, A-acetylglucosamine-thiazoline (NAG-thiazoline), has been described recently (5). The increased potency likely is because the compound already resembles the oxazoline intermediate before it is exposed to the enzyme. Macauley et al. 

Lin, C-C, ShimazaM, M, Heck, M-P, Aoki, S, Wang, R, Kimura, T, Ritzen, H, Takayama, S, Wu, S-H, Weitz-Schmidt, G, Wong, C-H, Synthesis of sialyl Lewis X mimetics and related structures using the glycosyl phosphite methodology and evaluation of E-selectin inhibition, J. Am. Chem. Soc., 118, 6826-6840, 1996. 

The glycopeptide mimetic structure was found to have antibacterial activity that exceeded that of the unglycosylated drosocin construct. As such, the authors concluded that altered carbohydrate structure outside of the conserved glycosyl-peptide bond was a tolerated modification in the biological system. 

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