title: Synthesis of a series of multivalent homo-, and heteroglycosides and their anti-adhesion activities.
abstract: 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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Haidian District, Beijing 100191, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Yan
authors.forename: Shan
authors.initials: S
authors.lastname: Niu
authors.forename: Yue-Tao
authors.initials: YT
authors.lastname: Zhao
authors.forename: Xiang-Bao
authors.initials: XB
authors.lastname: Meng
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Zhao
authors.forename: Zhong-Jun
authors.initials: ZJ
authors.lastname: Li
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D006027:Glycosides
keywords: CD11b; Cell adhesion; Heteroglycocluster; Homoglycocluster; Synthesis