title: Dendri-RAFTs: a second generation of cyclopeptide-based glycoclusters.
abstract: Synthetic glycoclusters and their related biological applications have stimulated increasing interest over the last decade. As a prerequisite to discovering active and selective therapeuticals, the development of multivalent glycoconjugates with diverse topologies is faced with inherent synthetic and structural characterisation difficulties. Here we describe a new series of molecularly-defined glycoclusters that were synthesized in a controlled manner using a robust and versatile divergent protocol. Starting from a Regioselectively Addressable Functionalized Template (RAFT) carrier, either a polylysine dendritic framework or a second RAFT, then 16 copies of βGal, αMan, βLac or cancer-related Thomsen-Freidenreich (αTF) antigen were successively conjugated within the same molecule using oxime chemistry. We thus obtained a new generation of dendri-RAFTs glycoclusters with high glycosidic density and variable spatial organizations. These compounds displaying 16 endgroups were unambiguously characterized by NMR spectroscopy and mass spectrometry. Further biological assays between a model lectin from Canavalia ensiformis (ConA) and mannosylated glycoclusters revealed a higher inhibition potency than the tetravalent counterpart, in particular for the hexadecavalent polylysine skeleton. Together with the efficiency of the synthetic and characterisation processes, this preliminary biological study provided clear evidence of promising properties that make the second generation of cyclopeptide-based glycoclusters attractive for biomedical applications.
authors.affiliation: Département de Chimie Moléculaire, UMR CNRS 5250 and ICMG FR 2607, Université Joseph Fourier, BP53, 38041 Grenoble Cedex 9, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bossu
authors.forename: Miroslav
authors.initials: M
authors.lastname: Šulc
authors.forename: Karel
authors.initials: K
authors.lastname: Křenek
authors.forename: Emilie
authors.initials: E
authors.lastname: Dufour
authors.forename: Julian
authors.initials: J
authors.lastname: Garcia
authors.forename: Nathalie
authors.initials: N
authors.lastname: Berthet
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
authors.forename: Vladimír
authors.initials: V
authors.lastname: Křen
authors.forename: Olivier
authors.initials: O
authors.lastname: Renaudet
mesh_terms: D032449:Canavalia / Q000737:chemistry; D002241:Carbohydrates / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis*
chemical_list: D002241:Carbohydrates; D010456:Peptides, Cyclic