‘Click chemistry’ synthesis of a library of 1,2,3-triazole-substituted galactose derivatives and their evaluation against Trypanosoma cruzi and its cell surface trans-sialidase |
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Authors: | Ivone Carvalho Peterson Andrade Vanessa L Campo Paulo MM Guedes Renata Sesti-Costa João S Silva Sergio Schenkman Simone Dedola Lionel Hill Martin Rejzek Sergey A Nepogodiev Robert A Field |
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Institution: | 1. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, USP, Av. Café S/N, CEP 14040-903, Ribeirão Preto, SP, Brazil;2. Faculdade de Medicina de Ribeirão Preto, USP, Av. Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, SP, Brazil;4. Department of Biological Chemistry, John Innes Centre, Colney Lane, Norwich, NR4 7UH, UK;5. Department of Metabolic Biology, John Innes Centre, Colney Lane, Norwich, NR4 7UH, UK |
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Abstract: | Trypanosoma cruzi trans-sialidase (TcTS) plays a key role in the recognition and invasion of host cells and in enabling the parasite to escape the human immune response. To explore this potential drug target, we have synthesized a small library of substrate analogues based on 1,4-disubstituted 1,2,3-triazole derivatives of galactose modified at either the C-1 or C-6 positions. This was achieved by coupling the appropriate azido-sugars with a panel of 23 structurally diverse terminal alkynes by using the copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction, giving a library of 46 derivatives in good to excellent yield and with complete regioselectivity. The sugar triazoles showed weak inhibition towards TcTS-catalyzed hydrolysis of 2′-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid in vitro (<40% inhibition at 1 mM concentration); many of the compounds assessed proved to be acceptor substrates for the enzyme. Despite this modest inhibitory activity, in vitro trypanocidal activity assays against the trypomastigote form of T. cruzi Y strain revealed several compounds active in the low 100s of μM range. Further assessment of these compounds against cultured mouse spleen cells suggests a specific mode of anti-parasite action rather than a generic cytotoxic effect. |
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