'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

Carvalho, Ivone, Andrade, Peterson, Campo, Vanessa L., Guedes, Paulo M. M., Sesti-Costa, Renata, Silva, João S., Schenkman, Sergio, Dedola, Simone, Hill, Lionel, Rejzek, Martin, Nepogodiev, Sergey A. and Field, Robert A. ORCID: https://orcid.org/0000-0001-8574-0275 (2010) '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 and Medicinal Chemistry, 18 (7). pp. 2412-2427. ISSN 0968-0896

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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.

Item Type:	Article
Additional Information:	Funding information: CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico-Brazil), FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo-Brazil) and the BBSRC (UK Biotehcnology and Biological Sciences Research Council).
Uncontrolled Keywords:	'click chemistry',galactose,trans-sialidase,triazole,trypanosoma cruzi,biochemistry,molecular medicine,molecular biology,pharmaceutical science,drug discovery,clinical biochemistry,organic chemistry ,/dk/atira/pure/subjectarea/asjc/1300/1303
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology Faculty of Science > School of Biological Sciences
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	06 Sep 2024 13:34
Last Modified:	25 Sep 2024 18:07
URI:	https://ueaeprints.uea.ac.uk/id/eprint/96592
DOI:	10.1016/j.bmc.2010.02.053

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