Artigo
'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
Fecha
2010-04-01Registro en:
Bioorganic & Medicinal Chemistry. Oxford: Pergamon-Elsevier B.V., v. 18, n. 7, p. 2412-2427, 2010.
0968-0896
10.1016/j.bmc.2010.02.053
WOS:000276258700006
Autor
Carvalho, Ivone
Andrade, Peterson
Campo, Vanessa L.
Guedes, Paulo M. M.
Sesti-Costa, Renata
Silva, Joao S.
Schenkman, Sergio [UNIFESP]
Dedola, Simone
Hill, Lionel
Rejzek, Martin
Nepogodiev, Sergey A.
Field, Robert A.
Institución
Resumen
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.