Sialyl mimetics

In a structure-based drug-discovery programme in the field of influenza virus neuraminidase inhibitors, researchers at BioCryst Pharmaceuticals discovered aminocarbafuranose sialyl mimetic 89 as a very potent candidate against influenza A and B viruses [17]. To arrive at this highly substituted compound in a non-racemic format, the viable route of Scheme 14 was executed. 

A short, scalable synthesis of carbapyranuronic acid 259, a sialyl mimetic compound related to the antiinfluenza drug Tamiflu , was developed by Kim s group [64] from (-)-shikimic acid 169 (Scheme 41). 

A similar approach was used in the synthesis of the sialyl Lewis X mimetics of type 85 (Scheme 13.22).66 Protein crystallization,67 conformational studies of sLex in solution68 and in bound form to E- and P-selectin69 as well as the study of structure-function relationships70,71 gave information about the functional groups of the sLex-epitope essential for the binding to the selectins. Synthesized mimetics must contain the three essential hydroxyl functions of the fucose. Sialic acid, galactose, and... 

Carrel F, Giraud S, Spertini O, Vogel P (2005) New non-hydrolyzable mimetics of sialyl Lewis x and their binding affinity to P-selection. Helv Chim Acta 87 1048-1070... 

Our interest in such methylene acetal derivatives is connected with the design of mimetics of Sialyl Lewis X (sLex) 1, a proposed native ligand for the selectin family of cell adhesion molecules. sLex-selectin interactions have been... 

FDP A was employed in a study of pancratistatin analogs to catalyze the formation of the D-threo stereochemistry (Scheme 5.24). When rhamnulose 1-phosphate aldolase (Rha 1-PA) was used the L-threo stereoisomer was obtained with excellent selectivity. Thus these two enzymes allow the stereoselective synthesis of the two threo-stereoisomers [44]. They were also utilised successfully for the synthesis of different diastereoisomers of sialyl Lewis X mimetics as se-lectin inhibitors. Not only the two threo-selective aldolases RAMA and Rha 1-PA, but also the D-erythro-selective Fuc 1-PA was employed. In this way it was possible to synthesise three of the four diastereoisomers enantioselectively (Scheme 5.25). The L-erythro stereochemistry as the only remaining diastereo-isomer was not prepared [45]. This is because the aldolase that might catalyze its formation, TDP A, is not very stereoselective and therefore often yields mixtures of diastereoisomers. 

Scheme 5.25 Aldolase-catalyzed synthesis of three stereoisomers of sialyl Lewis X mimetics.

Mimetics of sialyl Lewis X, the terminal tetrasaccharide of glycoproteins and glycolipids that are known to interact with selectins in the inflammatory process, have been efficiently synthesized through the use of the enzymatic aldol condensation (Scheme 5.26).29 This straightforward approach involved the condensation of mannosyl aldehyde derivatives with DHAP in the presence of DHAP-dependent aldolases. The aldehyde acceptors are generated from mannose by protection of the anomeric center as allyl ether, followed by... 

Scheme 5.26. (a) Synthesis of sialyl Lewis X (SLe1) mimetics. Conditions (a) allyl alcohol,... 

Scheme 5.50. Synthesis of sialyl Lewis X mimetics using L-threonine aldolase (LTA).

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]. 

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. 

De Vleeschauwer, M, Vaillancourt, M, Goudreau, N, Guindon, Y, Gravel, D, Design and synthesis of a new sialyl Lewis X mimetic how selective are the selectin receptors Bioorg. Med Chem. Lett., 11, 1109-1112, 2001. 

Toepfer, A, Kretzschmar, G, Bartnik, E, Synthesis of novel mimetics of the sialyl Lewis determinant, Tetrahedron Lett., 36, 9161-9164, 1995. 

Hanessian, S, Reddy, G V, Huynh, H K, Pan, J, Pedatella, S, Ernst, B, Kolb, H C, Design and synthesis of sialyl Le mimetics based on carbocyclic scaffolds derived from (-) quinic acid, Bioorg. Med. Chem. Lett, 1, 2729-2734, 1997. 

Huang, H, Wong, C-H, Synthesis of biologically active sialyl Lewis mimetics, J. Org. Chem., 60, 3100-3106, 1995. 

Tsai, C-Y, Park, W K C, Weitz-Schmidt, G, Ernst, B, Wong, C-H, Synthesis of sialyl Lewis mimetics using the Ugi four-component reaction, Bioorg. Med. Chem. Lett., 8, 2333-2338, 1998. 

Tsai, C-Y, Huang, X, Wong, C-H, Design and synthesis of cyclic sialyl Lewis X mimetics a remarkable enhancement of inhibition by pre-organizing all essential functional groups. Tetrahedron Lett., 41, 9499-9503, 2000. 

Kretzschmar, G, Toepfer, A, Hiils, C, Krause, M, Pitfalls in the synthesis and biological evaluation of sialyl Lewis mimetics as potential selectin antagonists. Tetrahedron, 53, 2485-2494, 1997. 

---