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Click chemistry oligomerisation of azido-alkyne-functionalised galactose accesses triazole-linked linear oligomers and macrocycles that inhibit Trypanosoma cruzi macrophage invasion.

Campo VL, Ivanova IM, Carvalho I, Lopes CD, Carneiro ZA, Saalbach G, Schenkman S, da Silva JS, Nepogodiev SA, Field RA - Tetrahedron (2015)

Bottom Line: Reaction of 2-(2-(2-azidoethoxy)ethoxy)ethyl 6-O-(prop-2-ynyl)-β-d-galactopyranoside (7) under CuAAC conditions gives rise to mixed cyclic and linear triazole-linked oligomers, with individual compounds up to d.p. 5 isolable, along with mixed larger oligomers.The triazole-linked oligomers-pseudo-galactooligomers-were demonstrated to be acceptor substrates for the multi-copy cell surface trans-sialidase of the human parasite Trypanosoma cruzi.In addition, these multivalent TcTS ligands were able to block macrophage invasion by T. cruzi.

View Article: PubMed Central - PubMed

Affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, USP, Av. Café S/N, CEP 14040-903, Ribeirão Preto, SP, Brazil.

ABSTRACT

Reaction of 2-(2-(2-azidoethoxy)ethoxy)ethyl 6-O-(prop-2-ynyl)-β-d-galactopyranoside (7) under CuAAC conditions gives rise to mixed cyclic and linear triazole-linked oligomers, with individual compounds up to d.p. 5 isolable, along with mixed larger oligomers. The linear compounds resolve en bloc from the cyclic materials by RP HPLC, but are separable by gel permeation chromatography. The triazole-linked oligomers-pseudo-galactooligomers-were demonstrated to be acceptor substrates for the multi-copy cell surface trans-sialidase of the human parasite Trypanosoma cruzi. In addition, these multivalent TcTS ligands were able to block macrophage invasion by T. cruzi.

No MeSH data available.


Schematic representation of cell surface-presented Trypanosoma cruzi trans-sialidase and potential for its' inhibition by 1,2,3-triazole-linked linear and cyclic pseudo-galactooligomers.
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fig1: Schematic representation of cell surface-presented Trypanosoma cruzi trans-sialidase and potential for its' inhibition by 1,2,3-triazole-linked linear and cyclic pseudo-galactooligomers.

Mentions: There is much current interest in the use of multivalent glycoconjugates as anti-pathogen agents18,24,25 and click chemistry presents interesting opportunities for the generation of oligomeric triazole-linked structures.26,27,27b CuAAC click chemistry has found application in the synthesis of analogues of cyclic oligosaccharides,27 with medium size macrocycles being prepared in moderate to good yields starting both from protected28,29 and ‘free’ sugar derivatives.30,31 There are only a few examples of the successful oligomerisation/polymerisation of such azide-alkyne-functionalised carbohydrates leading to linear oligomers, including recent proximity-driven click-polymerization of an 4-O-propargyl-β-d-galactopyranosyl azide in a crystal lattice32,33 and click-polymerisation of an open chain azido-alkyne derivative of gluconamide.34 We have previously shown that the cyclooligomerisation of azido-alkyne-functionalised sugars gives rise to relatively rigid 1,6-linked cyclic pseudo-galactooligosaccharides that are recognised by TcTS.31 In the present study, we wished to access linear oligomers and/or larger macrocycles, in order to span a greater area that might more adequately map to the distribution of trans-sialidase on the parasite cell surface, so blocking trans-sialidase-action and associated infection processes35 (Fig. 1). Here we have designed linkers between sugar and azide functionality, in contrast to our previous work. We opted for ethylene glycol-based linkers to reduce the potential for non-specific interactions with proteins and membrane components.36 We anticipated that these flexible linkers might also promote oligomerisation at the expense of cyclisation. Here we report the chemical synthesis of azido-alkyne-functionalised galactose monomer 7, CuAAC click reactions thereof and characterisation of the resulting triazole-linked oligomers. Finally, assessment of the interaction of these triazole-linked materials with TcTS is reported, along with initial assessment of their ability to block macrophage invasion by T. cruzi parasites.


Click chemistry oligomerisation of azido-alkyne-functionalised galactose accesses triazole-linked linear oligomers and macrocycles that inhibit Trypanosoma cruzi macrophage invasion.

Campo VL, Ivanova IM, Carvalho I, Lopes CD, Carneiro ZA, Saalbach G, Schenkman S, da Silva JS, Nepogodiev SA, Field RA - Tetrahedron (2015)

Schematic representation of cell surface-presented Trypanosoma cruzi trans-sialidase and potential for its' inhibition by 1,2,3-triazole-linked linear and cyclic pseudo-galactooligomers.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4542550&req=5

fig1: Schematic representation of cell surface-presented Trypanosoma cruzi trans-sialidase and potential for its' inhibition by 1,2,3-triazole-linked linear and cyclic pseudo-galactooligomers.
Mentions: There is much current interest in the use of multivalent glycoconjugates as anti-pathogen agents18,24,25 and click chemistry presents interesting opportunities for the generation of oligomeric triazole-linked structures.26,27,27b CuAAC click chemistry has found application in the synthesis of analogues of cyclic oligosaccharides,27 with medium size macrocycles being prepared in moderate to good yields starting both from protected28,29 and ‘free’ sugar derivatives.30,31 There are only a few examples of the successful oligomerisation/polymerisation of such azide-alkyne-functionalised carbohydrates leading to linear oligomers, including recent proximity-driven click-polymerization of an 4-O-propargyl-β-d-galactopyranosyl azide in a crystal lattice32,33 and click-polymerisation of an open chain azido-alkyne derivative of gluconamide.34 We have previously shown that the cyclooligomerisation of azido-alkyne-functionalised sugars gives rise to relatively rigid 1,6-linked cyclic pseudo-galactooligosaccharides that are recognised by TcTS.31 In the present study, we wished to access linear oligomers and/or larger macrocycles, in order to span a greater area that might more adequately map to the distribution of trans-sialidase on the parasite cell surface, so blocking trans-sialidase-action and associated infection processes35 (Fig. 1). Here we have designed linkers between sugar and azide functionality, in contrast to our previous work. We opted for ethylene glycol-based linkers to reduce the potential for non-specific interactions with proteins and membrane components.36 We anticipated that these flexible linkers might also promote oligomerisation at the expense of cyclisation. Here we report the chemical synthesis of azido-alkyne-functionalised galactose monomer 7, CuAAC click reactions thereof and characterisation of the resulting triazole-linked oligomers. Finally, assessment of the interaction of these triazole-linked materials with TcTS is reported, along with initial assessment of their ability to block macrophage invasion by T. cruzi parasites.

Bottom Line: Reaction of 2-(2-(2-azidoethoxy)ethoxy)ethyl 6-O-(prop-2-ynyl)-β-d-galactopyranoside (7) under CuAAC conditions gives rise to mixed cyclic and linear triazole-linked oligomers, with individual compounds up to d.p. 5 isolable, along with mixed larger oligomers.The triazole-linked oligomers-pseudo-galactooligomers-were demonstrated to be acceptor substrates for the multi-copy cell surface trans-sialidase of the human parasite Trypanosoma cruzi.In addition, these multivalent TcTS ligands were able to block macrophage invasion by T. cruzi.

View Article: PubMed Central - PubMed

Affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, USP, Av. Café S/N, CEP 14040-903, Ribeirão Preto, SP, Brazil.

ABSTRACT

Reaction of 2-(2-(2-azidoethoxy)ethoxy)ethyl 6-O-(prop-2-ynyl)-β-d-galactopyranoside (7) under CuAAC conditions gives rise to mixed cyclic and linear triazole-linked oligomers, with individual compounds up to d.p. 5 isolable, along with mixed larger oligomers. The linear compounds resolve en bloc from the cyclic materials by RP HPLC, but are separable by gel permeation chromatography. The triazole-linked oligomers-pseudo-galactooligomers-were demonstrated to be acceptor substrates for the multi-copy cell surface trans-sialidase of the human parasite Trypanosoma cruzi. In addition, these multivalent TcTS ligands were able to block macrophage invasion by T. cruzi.

No MeSH data available.