'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

被引:128
作者
Carvalho, Ivone [1 ]
Andrade, Peterson [1 ]
Campo, Vanessa L. [1 ]
Guedes, Paulo M. M. [2 ]
Sesti-Costa, Renata [2 ]
Silva, Joao S. [2 ]
Schenkman, Sergio [3 ]
Dedola, Simone [4 ]
Hill, Lionel [5 ]
Rejzek, Martin [4 ]
Nepogodiev, Sergey A. [4 ]
Field, Robert A. [4 ]
机构
[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Ribeirao Preto, SP, Brazil
[2] Univ Sao Paulo, Fac Med Ribeirao Preto, BR-14049900 Ribeirao Preto, SP, Brazil
[3] Univ Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, BR-04023062 Sao Paulo, Brazil
[4] John Innes Ctr, Dept Biol Chem, Norwich NR4 7UH, Norfolk, England
[5] John Innes Ctr, Dept Metab Biol, Norwich NR4 7UH, Norfolk, England
基金
英国生物技术与生命科学研究理事会; 巴西圣保罗研究基金会;
关键词
Trypanosoma cruzi; Trans-sialidase; Galactose; Triazole; 'Click chemistry'; CHEMOENZYMATIC SYNTHESIS; SUBSTRATE-SPECIFICITY; TERMINAL ALKYNES; INHIBITORS; OLIGOSACCHARIDES; CYCLOADDITION; TRIAZOLE; ENZYME; AZIDES; DISCOVERY;
D O I
10.1016/j.bmc.2010.02.053
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Ltd. All rights reserved.
引用
收藏
页码:2412 / 2427
页数:16
相关论文
共 63 条
[1]   Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo [J].
Agustí, R ;
París, G ;
Ratier, L ;
Frasch, ACC ;
de Lederkremer, RM .
GLYCOBIOLOGY, 2004, 14 (07) :659-670
[2]   Potent Fluoro-oligosaccharide Probes of Adhesion in Toxoplasmosis [J].
Allman, Sarah A. ;
Jensen, Henrik H. ;
Vijayakrishnan, Balakumar ;
Garnett, James A. ;
Leon, Ester ;
Liu, Yan ;
Anthony, Daniel C. ;
Sibson, Nicola R. ;
Feizi, Ten ;
Matthews, Stephen ;
Davis, Benjamin G. .
CHEMBIOCHEM, 2009, 10 (15) :2522-2529
[3]   Structural insights into the catalytic mechanism of Trypanosoma cruzi trans-sialidase [J].
Amaya, MF ;
Watts, AG ;
Damager, I ;
Wehenkel, A ;
Nguyen, T ;
Buschiazzo, A ;
Paris, G ;
Frasch, AC ;
Withers, SG ;
Alzari, PM .
STRUCTURE, 2004, 12 (05) :775-784
[4]  
Blanco JLJ, 1997, CARBOHYD RES, V303, P367, DOI 10.1016/S0008-6215(97)00176-6
[5]   6-AzidO D-galactose transfer to N-acetyl-D-glucosamine derivative using commercially available β-1,4-galactosyltransferase [J].
Bosco, Michaeel ;
Le Gall, Sophie ;
Rihouey, Christophe ;
Couve-Bonnaire, Samuel ;
Bardor, Muriel ;
Lerouge, Patrice ;
Pannecoucke, Xavier .
TETRAHEDRON LETTERS, 2008, 49 (14) :2294-2297
[6]  
BRENER Z., 1962, REV INST MED TROP SAO PAULO, V4, P389
[7]   Structural basis of sialyltransferase activity in trypanosomal sialidases [J].
Buschiazzo, A ;
Tavares, GA ;
Campetella, O ;
Spinelli, S ;
Cremona, ML ;
París, G ;
Amaya, MF ;
Frasch, ACC ;
Alzari, PM .
EMBO JOURNAL, 2000, 19 (01) :16-24
[8]   The crystal structure and mode of action of trans-sialidase, a key enzyme in Trypanosoma cruzi pathogenesis [J].
Buschiazzo, A ;
Amaya, MF ;
Cremona, ML ;
Frasch, AC ;
Alzari, PM .
MOLECULAR CELL, 2002, 10 (04) :757-768
[9]   Chemical and chemoenzymatic synthesis of glycosyl-amino acids and glycopeptides related to Trypanosoma cruzi mucins [J].
Campo, Vanessa Leiria ;
Carvalho, Ivone ;
Allman, Sarah ;
Davis, Benjamin G. ;
Field, Robert A. .
Organic and Biomolecular Chemistry, 2007, 5 (16) :2645-2657
[10]  
CAMPO VL, 2006, MODERN BIOTECHNOLOGY, P27