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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.


Inhibition of T. cruzi invasion of bovine macrophages in the presence of 1,4/1,5-triazole-linked cyclic dimers (C2), trimer (C3), tetramer (C4), pentamer (C5), hexamer (C6), heptamer (C7) and a series of mixed 1,4/1,5-triazole-linked linear oligomers. A: Parasites were applied to macrophages without () or with () pre-incubation with triazoles and following 6 days incubation the numbers of trypomastigotes in the medium was quantified as % reduction in the number of parasite released from macrophages (% inhibition). B: Parasites and triazoles were applied to macrophages and the number of amastigotes present inside the macrophages was quantified as an average number of parasite per macrophage (T. cruzi/Macrophage).
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fig4: Inhibition of T. cruzi invasion of bovine macrophages in the presence of 1,4/1,5-triazole-linked cyclic dimers (C2), trimer (C3), tetramer (C4), pentamer (C5), hexamer (C6), heptamer (C7) and a series of mixed 1,4/1,5-triazole-linked linear oligomers. A: Parasites were applied to macrophages without () or with () pre-incubation with triazoles and following 6 days incubation the numbers of trypomastigotes in the medium was quantified as % reduction in the number of parasite released from macrophages (% inhibition). B: Parasites and triazoles were applied to macrophages and the number of amastigotes present inside the macrophages was quantified as an average number of parasite per macrophage (T. cruzi/Macrophage).

Mentions: Parasites were mixed with bovine macrophages and triazole-linked oligomers, with or without a pre-incubation of the parasite and oligomers; where a pre-incubation was employed, free triazole-linked oligomers were removed by washing before adding the parasites to macrophages. The parasites were left to invade the macrophages and after 6 days, the trypomastigote form found in the medium was removed and counted. As shown in Fig. 4 A (), the incubation of parasite with triazole-linked oligomers substantially inhibited the invasion of macrophage by parasites (>90% for trimer-hexamer). To rule out a direct impact of the triazole-linked compounds on the macrophages, pre-incubation of parasites with triazoles, plus washing to remove excess triazole, was assessed. While the impact on parasite invasion was more modest than when the triazole was present throughout (Fig. 4 A ), this is to be expected given the dramatic reduction in concentration of the inhibitor in these experiments. Gratifyingly, inhibition of macrophage invasion was still pronounced.


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)

Inhibition of T. cruzi invasion of bovine macrophages in the presence of 1,4/1,5-triazole-linked cyclic dimers (C2), trimer (C3), tetramer (C4), pentamer (C5), hexamer (C6), heptamer (C7) and a series of mixed 1,4/1,5-triazole-linked linear oligomers. A: Parasites were applied to macrophages without () or with () pre-incubation with triazoles and following 6 days incubation the numbers of trypomastigotes in the medium was quantified as % reduction in the number of parasite released from macrophages (% inhibition). B: Parasites and triazoles were applied to macrophages and the number of amastigotes present inside the macrophages was quantified as an average number of parasite per macrophage (T. cruzi/Macrophage).
© Copyright Policy - CC BY
Related In: Results  -  Collection

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

fig4: Inhibition of T. cruzi invasion of bovine macrophages in the presence of 1,4/1,5-triazole-linked cyclic dimers (C2), trimer (C3), tetramer (C4), pentamer (C5), hexamer (C6), heptamer (C7) and a series of mixed 1,4/1,5-triazole-linked linear oligomers. A: Parasites were applied to macrophages without () or with () pre-incubation with triazoles and following 6 days incubation the numbers of trypomastigotes in the medium was quantified as % reduction in the number of parasite released from macrophages (% inhibition). B: Parasites and triazoles were applied to macrophages and the number of amastigotes present inside the macrophages was quantified as an average number of parasite per macrophage (T. cruzi/Macrophage).
Mentions: Parasites were mixed with bovine macrophages and triazole-linked oligomers, with or without a pre-incubation of the parasite and oligomers; where a pre-incubation was employed, free triazole-linked oligomers were removed by washing before adding the parasites to macrophages. The parasites were left to invade the macrophages and after 6 days, the trypomastigote form found in the medium was removed and counted. As shown in Fig. 4 A (), the incubation of parasite with triazole-linked oligomers substantially inhibited the invasion of macrophage by parasites (>90% for trimer-hexamer). To rule out a direct impact of the triazole-linked compounds on the macrophages, pre-incubation of parasites with triazoles, plus washing to remove excess triazole, was assessed. While the impact on parasite invasion was more modest than when the triazole was present throughout (Fig. 4 A ), this is to be expected given the dramatic reduction in concentration of the inhibitor in these experiments. Gratifyingly, inhibition of macrophage invasion was still pronounced.

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.