'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

'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

Author Carvalho, Ivone Google Scholar
Andrade, Peterson Google Scholar
Campo, Vanessa L. Google Scholar
Guedes, Paulo M. M. Google Scholar
Sesti-Costa, Renata Google Scholar
Silva, Joao S. Google Scholar
Schenkman, Sergio Autor UNIFESP Google Scholar
Dedola, Simone Google Scholar
Hill, Lionel Google Scholar
Rejzek, Martin Google Scholar
Nepogodiev, Sergey A. Google Scholar
Field, Robert A. Google Scholar
Institution Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
John Innes Ctr
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)-alpha-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 mu M 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. (C) 2010 Elsevier B.V. All rights reserved.
Keywords Trypanosoma cruzi
Trans-sialidase
Galactose
Triazole
'Click chemistry'
Language English
Sponsor Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
BBSRC (UK Biotehcnology and Biological Sciences Research Council)
Date 2010-04-01
Published in Bioorganic & Medicinal Chemistry. Oxford: Pergamon-Elsevier B.V., v. 18, n. 7, p. 2412-2427, 2010.
ISSN 0968-0896 (Sherpa/Romeo, impact factor)
Publisher Elsevier B.V.
Extent 2412-2427
Origin http://dx.doi.org/10.1016/j.bmc.2010.02.053
Access rights Closed access
Type Article
Web of Science ID WOS:000276258700006
URI http://repositorio.unifesp.br/handle/11600/32417

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