Binding of triazole-linked galactosyl arylsulfonamides to galectin-3 affects Trypanosoma cruzi cell invasion. Issue 21 (1st November 2017)

• Record Type: Journal Article
• Authors: Marchiori, Marcelo Fiori; Riul, Thalita B.; Oliveira Bortot, Leandro; Andrade, Peterson; Junqueira, Getúlio G.; Foca, Giuseppina; Doti, Nunzianna; Ruvo, Menotti; Dias-Baruffi, Marcelo; Carvalho, Ivone; Campo, Vanessa Leiria
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 21(2017)
• Page Start: 6049
• Page End: 6059
• Publication Date: 2017-11-01
• Subjects: DAKLRLIHCPJQIH-BEBHXBEKSA-N -- JYJSFVHCILSZDP-HBWZYELFSA-N -- RJWNSTFHZRPHGU-LOVNCYQGSA-N -- ZELZBHUNDZYLGW-YSZROVPYSA-N -- PHOBCMQYTHOLNE-RZTPSRECSA-N -- NRGFYMRUMFYKL-BVPMPBNFSA-N -- KWOGVBPWHWLVFW-YODPDHEQSA-N; Triazole -- Galactosyl arylsulfonamides -- "Click Chemistry" -- Trypanosoma cruzi -- Cell invasion -- Galectin-3 -- trans-Sialidase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.09.042
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The synthesis of the O-3 triazole-linked galactosyl arylsulfonamides1 –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-βGalOMe. Inhibition assays of T. cruzi cell invasion with compounds1 –7 showed reduced values of infection index (∼20) for compounds3 and5, bearing the corresponding 5-methylisoxazole and 2, 4-dimethoxypyrimidine groups, which also presented higher binding affinities to galectin-3 (EC50 17–18 μM) in Corning Epic label-free assays. In agreement with experimental results, the assessment of the theoretical binding of compounds1 –7 to galectin-3 by MM/PBSA method displayed higher affinities for compounds3 (−9.7 kcal/mol) and5 (−11.1 kcal/mol). Overall, these achievements highlight compounds3 and5 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.