Tetrasaccharide mimic

Fluorogenic compound (56) for transketolase assays has been prepared making use of FruA specificity [123]. Pendant anionically charged chains have been extended from O- or C-glycosidic aldehydes to furnish low molecular weight mimics of the sialyl Lewis X tetrasaccharide such as (SS) (Figure 10.23) [124], Other higher carbon... 

Parallel synthesis of 62 different fucosylated tripeptides resulted in two ligands with submicromolar affinity for the P-selectin however, the desired activity for the E-selectin was not observed.98 For the E-selectin selectivity, it was necessary to incorporate a hydroxyl group that mimics the 4-hydroxyl of the central Gal in SLex in addition to a Fuc-residue and a carboxylate to obtain ligands with > 10-fold increased activity over that of the SLex tetrasaccharide.81 One of the best ligands was obtained from Thr(a-Fuc)-OEt, which was first /V-acylated with a hydroxyl amino acid and then elongated with a di-acid to furnish the acid mimic of the sialic acid carboxylate (Fig. 14.4). This approach was further developed as a solid-phase method where the molecule was linked to a solid support through the invariable fucosyl moiety.99... 

With knowledge of the importance of sLe" functional groups for complexation, mimics of the tetrasaccharide have been synthesized... 

Based on these results, and with the aim of obtaining structurally simplified and pharmacokinetically improved MAG antagonists, a number of mimics of tetrasaccharide 67 were prepared and their affinity towards MAG tested in the fluorescent hapten inhibition assay [58] relative to 67 [70,71]. fii these studies, the Gal-P(l-3)-GaWAc core was simplified, the a(2-6)-linked sialic acid was replaced... 

Finally, concomitant modifications at the site of the a(2-3)- as well as at the a(2-6)-linked sialic acid proved the additivity of the beneficial interactions, leading to mimic 84 (entry 15) exhibiting a more than 300-fold enhanced affinity compared to the parent tetrasaccharide 67. Similar to previous findings [73], the p-chloro substituent on the benzamide in 85 (entry 16) led to a further significant enhancement of the affinity compared to 84 (rlP 377 vs 314). The synthesis of compound 85 is depicted in Scheme 4. 

The reverse strategy has recently been reported by the same group for the preparation of a similar C-mimic of the P(l 6) tetragalactoside as shown in Scheme 2 [49]. Condensation of the D-galactopyranosyl-derived phosphonium salt 99 and aldehyde 68 led to the unsaturated dimer 100 (Scheme 23). Repetition of the sequence twice with phosphonium salt 99 furnished tetramer 101. These steps are, however, characterized by low coupling efficiencies (36% for the trimer and 11% for the tetramer) mostly because of the base-induced a,P-unsaturation of the aldehyde substrates. The desired tetrasaccharide 102 was then obtained after standard deprotection and double-bond hydrogenation. 

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