Synthesis of the Tetrasaccharide Cap Domain of the Antigenic Lipophosphoglycan of Leishmania donovani Parasite

Upreti, Mani; Ruhela, Dipali; Vishwakarma, Ram A.

doi:10.1016/s0040-4020(00)00609-8

Cited by 55 publications

(27 citation statements)

References 43 publications

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“…was added to a mixture of trichloroacetimidate sugar donor [39] (1g, 2.0 mmol) and 2-hydroxyethyl methacrylate (1.2 eq) in dichloromethane at room temperature. The reaction mixture was stirred at room temperature for 20 min and then quenched by the addition of triethylamine.…”

Section: Methodsmentioning

confidence: 99%

In vivo targeting of alveolar macrophages via RAFT-based glycopolymers

Song¹,

Manganiello²,

Chow³

et al. 2012

Biomaterials

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Targeting cell populations via endogenous carbohydrate receptors is an appealing approach for drug delivery. However, to be effective, this strategy requires the production of high affinity carbohydrate ligands capable of engaging with specific cell-surface lectins. To develop materials that exhibit high affinity towards these receptors, we synthesized glycopolymers displaying pendant carbohydrate moieties from carbohydrate-functionalized monomer precursors via reversible addition-fragmentation chain transfer (RAFT) polymerization. These glycopolymers were fluorescently labeled and used to determine macrophage-specific targeting both in vitro and in vivo. Mannose- and N-acetylglucosamine-containing glycopolymers were shown to specifically target mouse bone marrow-derived macrophages (BMDMs) in vitro in a dose-dependent manner as compared to a galactose-containing glycopolymer (30- and 19-fold higher uptake, respectively). In addition, upon macrophage differentiation, the mannose glycopolymer exhibited enhanced uptake in M2-polarized macrophages, an anti-inflammatory macrophage phenotype prevalent in injured tissue. This carbohydrate-specific uptake was retained in vivo, as alveolar macrophages demonstrated 6-fold higher internalization of mannose glycopolymer, as compared to galactose, following intratracheal administration in mice. We have shown the successful synthesis of a class of functional RAFT glycopolymers capable of macrophage-type specific uptake both in vitro and in vivo, with significant implications for the design of future targeted drug delivery systems.

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Section: Methodsmentioning

confidence: 99%

In vivo targeting of alveolar macrophages via RAFT-based glycopolymers

Song¹,

Manganiello²,

Chow³

et al. 2012

Biomaterials

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“…Chromatography of the residue (EtOAc, then dichloromethane-MeOH 98 : 2) gave 20a as an off-white solid (76 mg, 62%); [a] 169.8,169.7,169.4,168.2,166.6 (each CO),142.2 (aromatic C),133.4 (CH),129.4 (aromatic CH),117.7 (CH 2 ),100.0,99.7,80.5,77.4,71.9,71.0 (each CH), 70.1 (CH 2 ), 69. 8,69.7,69.0,65.6 (each CH), 3631-3374, 2966, 1751, 1670, 1510, 1438, 1373, 1223, 1040 cm -1 .…”

Section: Experimental Allyl 2346-tetra-o-acetyl-a-d-mannopyranosylmentioning

confidence: 99%

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

et al. 2009

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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.

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“…The only way these issues can be sorted out unambiguously is by using structurally defined GPIs and their domains obtained by chemical synthesis. In a program to address the above-mentioned issue, we have initiated efforts (17)(18)(19)(20)(21)(22) …”

mentioning

confidence: 99%