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'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.

Bioorganic & medicinal chemistry (2010-03-26)
Ivone Carvalho, Peterson Andrade, Vanessa L Campo, Paulo M M Guedes, Renata Sesti-Costa, João S Silva, Sergio Schenkman, Simone Dedola, Lionel Hill, Martin Rejzek, Sergey A Nepogodiev, Robert A Field
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 1mM 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 muM 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Pyridoxal 5′-phosphate hydrate, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
N-Acetyl-2,3-dehydro-2-deoxyneuraminic acid, ≥93%
Sigma-Aldrich
Pyridoxal 5′-phosphate hydrate, ≥98%