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

作者：Marchiori Marcelo Fiori; Riul Thalita B; Bortot Leandro Oliveira; Andrade Peterson; Junqueira Getulio G; Foca Giuseppina; Doti Nunzianna; Ruvo Menotti; Dias Baruffi Marcelo; Carvalho Ivone; Campo Vanessa Leiria^*

来源：Bioorganic & Medicinal Chemistry, 2017, 25(21): 6049-6059.

DOI：10.1016/j.bmc.2017.09.042

• Triazole
• Galactosyl arylsulfonamides
• Click Chemistry
• Trypanosoma cruzi
• Cell invasion
• Galectin-3
• trans-Sialidase

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.

• 出版日期2017-11-1