Binding of triazole-linked galactosyl arylsulfonamides to galectin-3 affects Trypanosoma cruzi cell invasion

Autor(es):Mostrar menos -

Marchiori, Marcelo Fiori ^[1] ; Riul, Thalita B. ^[1] ; Bortot, Leandro Oliveira ^[1] ; Andrade, Peterson ^[1] ; Junqueira, Getulio G. ^[1] ; Foca, Giuseppina ^[2] ; Doti, Nunzianna ^[2] ; Ruvo, Menotti ^[2] ; Dias-Baruffi, Marcelo ^[1] ; Carvalho, Ivone ^[1] ; Campo, Vanessa Leiria ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, Av Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] CNR, Ist Biostrutture & Bioimmagini, Via Mezzocannone 16, I-80134 Naples - Italy

• Tipo de documento: Artigo Científico
• Fonte: Bioorganic & Medicinal Chemistry; v. 25, n. 21, p. 6049-6059, NOV 1 2017.
• Citações Web of Science: 3

Resumo

The synthesis of the O-3 triazole-linked galactosyl arylsulfonamides 1-7 as potential inhibitors of Trypanosoma cruzi cell invasion is described. These target compounds were synthesized by Cu(I)-catalysed azide-alkyne cycloaddition reaction ('click chemistry') between different azide arylsulfonamides and the alkyne-based sugar 3-O-propynyl-bGalOMe. Inhibition assays of T. cruzi cell invasion with compounds 1-7 showed reduced values of infection index (similar to 20) for compounds 3 and 5, bearing the corresponding 5-methylisoxazole and 2,4-dimethoxypyrimidine groups, which also presented higher binding affinities to galectin-3 (EC50 17-18 mu M) in Corning Epic label-free assays. In agreement with experimental results, the assessment of the theoretical binding of compounds 1-7 to galectin-3 by MM/PBSA method displayed higher affinities for compounds 3 (- 9.7 kcal/mol) and 5 (- 11.1 kcal/mol). Overall, these achievements highlight compounds 3 and 5 as potential T. cruzi cell invasion blockers by means of a galectin-3 binding-related mechanism, revealing galectin-3 as an important host target for design of novel anti-trypanosomal agents. (C) 2017 Elsevier Ltd. All rights reserved. (AU)

• Processo FAPESP: 12/19390-0 - Desenvolvimento de glicoconjugados de mucinas com aplicações diagnósticas e terapêuticas em distrofias musculares e câncer
• Beneficiário: Vanessa Leiria Campo
• Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores