Orthogonal dual thiol-chloroacetyl and thiol-ene couplings for the sequential one-pot assembly of heteroglycoclusters.

We describe the first one-pot orthogonal strategy to prepare well-defined cyclopeptide-based heteroglycoclusters (hGCs) from glycosyl thiols. Both thiol-chloroactetyl coupling (TCC) and thiol-ene coupling (TEC) have been used to decorate cyclopeptides regioselectively with diverse combination of sugars. We demonstrate that the reaction sequence starting with TCC can be performed one-pot whereas the reverse sequence requires a purification step after the TEC reaction. The versatility of this orthogonal strategy has been demonstrated through the synthesis of diverse hGCs displaying alternating binary combinations of α-D-Man or ß-D-GlcNAc, thus providing rapid access to attractive heteroglycosylated platforms for diverse biological applications.

Synthesis of heteroglycoclusters by using orthogonal chemoselective ligations.

Synthetic heteroglycoclusters are being subjected to increasing interest due to their potential to serve as selective ligands for carbohydrate-binding proteins. In this paper, we describe an expedient strategy to prepare cyclopeptides displaying well-defined distributions and combinations of carbohydrates. By using both oxime ligation and copper(I)-catalyzed alkyne-azide cycloaddition, two series of compounds bearing binary combinations of αMan, αFuc or ßLac in an overall tetravalent presentation, and either 2:2 or 3:1 relative proportions, have been prepared.

Heteroglycoclusters With Dual Nanomolar Affinities for the Lectins LecA and LecB From Pseudomonas aeruginosa.

Multivalent structures displaying different instead of similar sugar units, namely heteroglycoclusters (hGCs), are stimulating the efforts of glycochemists for developing compounds with new biological properties. Here we report a four-step strategy to synthesize hexadecavalent hGCs displaying eight copies of αFuc and ßGal. These compounds were tested for the binding to lectins LecA and LecB from Pseudomonas aeruginosa. While parent fucosylated (19) and galactosylated (20) homoclusters present nanomolar affinity with LecB and LecA, respectively, we observed that hGCs combining these sugars (11 and 13) maintain their binding potency with both lectins despite the presence of an unspecific sugar. The added multivalency is therefore not a barrier for efficient recognition by bacterial receptors and it opens the route for adding different sugars that can be selected for their immunomodulatory properties.

Synthesis of a series of novel heteroglycoclusters and homoglycoclusters and the study of their anti-adhesion activities.

A new series of mixed-type heteroglycoclusters containing mannose and lactose were synthesized. In the synthesis of rigid scaffold of heteroglycocluster, we found that trans-isomer could be prepared stereoselectively by means of Grubbs olefin cross-metathesis reactions. Moreover, sequential acylation using cyclic anhydride as scaffold could give cis-isomer. These two methods may provide complementarity of stereochemistry in heteroglycocluster assembling. The anti-adhesion activities of these compounds were assessed by Surface Plasmon Resonance (SPR) and static state cell-based adhesion assay. These results indicated that the rigid scaffold might not affect the anti-adhesion activities.

Synthesis of a series of multivalent homo-, and heteroglycosides and their anti-adhesion activities.

Adhesion of leukocytes to endothelium plays an important role in inflammatory diseases. We previously found that the tetravalent lactoside Gu-4 was able to inhibit leukocyte-endothelial cell adhesion significantly and that CD11b was the target of Gu-4 on the surface of leukocytes. In this report, we aimed to explore the relationship between structural characteristics of glycoclusters and anti-adhesion activity. Using selective glycosylation method and convergent strategy, we synthesized a new series of homoglycoclusters and heteroglycoclusters with diverse structures. And the bioactivities of these compounds were assessed by a static state cell-based adhesion assay. We found that when the linked saccharide fragments are the same, the anti-adhesion activities of compounds with flexible linkers were stronger than those with rigid scaffold such as the benzene ring, and the best flexible linker in the tested compounds was L-glutamic acid. When l-glutamic acid was employed as the linker, glycoclusters with four valences, but not other valences, exhibited the most significant anti-adhesion activity; however, no significant differences in anti-adhesion activity were found among the tetravalentglycosides that were made by linking glucose (32), mannose (TMa-4), cellobiose (34), or lactose (Gu-4). Thus, we conclude that a flexible linker with proper length, such as that of L-glutamic acid, and the linking of four saccharide fragments might be the preferable structural characteristics for the glycocluster compounds with potent anti-adhesion activity.