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Phenylenediamine-based bivalent glycocyclophanes: synthesis and analysis of the influence of scaffold rigidity and ligand spacing on lectin binding in cell systems with different glycomic profiles

Andre, Sabine and Velasco-Torrijos, Trinidad and Leyden, Rosaria and Gouin, Sebastien and Tosin, Manuela and Murphy, Paul V. and Gabius, Hans-Joachim (2009) Phenylenediamine-based bivalent glycocyclophanes: synthesis and analysis of the influence of scaffold rigidity and ligand spacing on lectin binding in cell systems with different glycomic profiles. Organic & Biomolecular Chemistry, 7. pp. 4715-4725. ISSN 1477-0520

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Abstract

The conjugation of carbohydrates to synthetic scaffolds has the goal of preparing potent inhibitors of lectin binding. We herein report the synthesis of a panel of bivalent compounds (cyclophane and terephthalamide-derivatives) then used to establish the influence of scaffold flexibility on respective inhibitory potency in a medically relevant test system. Synthetic routes to two phenylenediamine-based glycocyclophanes involving Ugi reactions of glucuronic acid derivatives and subsequent ring closing metathesis are described, as are improvements for producing terephthalamide-based carbohydrate carriers. Assays were performed with human tumour cells measuring quantitatively the influence of the test compounds on fluorescent surface staining by labelled lectins. Biological evaluation using two different lines of cancer cells as well as cells with known alterations in the glycomic profile (cells treated with an inhibitor of glycan processing and a glycosylation mutant) reduced the risk of generating premature generalizations regarding inhibitor potency. Bioactivity relative to free mannose was invariably determined for the synthetic compounds. A clear trend for enhanced inhibitory properties for macrocyclic compounds compared to non-macrocyclic derivatives was discerned for one type of glycocyclophane. Herein we also document the impact of altering the spacing between the mannose residues, altering cell surface ligand density and cell-type reactivity. The applied strategy for the cell assays is proposed to be of general importance in the quest to identify medically relevant lectin inhibitors.

Item Type: Article
Keywords: Phenylenediamine-based bivalent glycocyclophanes; synthesis; analysis; scaffold rigidity; ligand spacing; lectin binding; cell systems; glycomic profiles;
Subjects: Science & Engineering > Chemistry
Item ID: 2116
Depositing User: Dr. Trinidad Velasco-Torrijos
Date Deposited: 21 Sep 2010 13:47
Journal or Publication Title: Organic & Biomolecular Chemistry
Publisher: Royal Society of Chemistry
Refereed: Yes
URI:

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