title: Synthetic 1,2,3-triazole-linked glycoconjugates bind with high affinity to human galectin-3.
abstract: This work describes the synthesis of the 1,2,3-triazole amino acid-derived-3-O-galactosides 1-6 and the 1,2,3-triazole di-lactose-derived glycoconjugate 7 as potential galectin-3 inhibitors. The target compounds were synthesized by Cu(I)-catalyzed azide-alkyne cycloaddition reaction ('click chemistry') between the azido-derived amino acids N3-ThrOBn, N3-PheOBn, N3-N-Boc-TrpOBn, N3-N-Boc-LysOBn, N3-O-tBu-AspOBn and N3-l-TyrOH, and the corresponding alkyne-based sugar 3-O-propynyl-GalOMe, as well as by click chemistry reaction between the azido-lactose and 2-propynyl lactose. Surface plasmon resonance (SPR) assays showed that all synthetic glycoconjugates 1-7 bound to galectin-3 with high affinity, but the highest binders were the amino acids-derived glycoconjugates 2 (KD 7.96μM) and 4 (KD 4.56μM), and the divalent lactoside 7 (KD1 0.15μM/KD2 19μM). Molecular modeling results were in agreement with SPR assays, since more stable interactions with galectin-3 were identified for glycoconjugates 2, 4 and 7. Regarding compounds 2 and 4, they established specific cation-π (Arg144) and ionic (Asp148) interactions, whereas glycoconjugate 7 was capable to bridge two independent galectin-3 CRDs, creating a non-covalent cross-link between two monomers and, thus, reaching a submicromolar affinity towards galectin-3.
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, USP, Av. Café S/N, CEP: 14040-903, Ribeirão Preto, SP, Brazil.
authors.forename: Marcelo Fiori
authors.initials: MF
authors.lastname: Marchiori
authors.affiliation: Instituto de Química-Unicamp, R. Josué de Castro s/n°, Cidade Universitária, CEP: 13083-861, Campinas, SP, Brazil.
authors.forename: Dênio Emanuel Pires
authors.initials: DE
authors.lastname: Souto
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, USP, Av. Café S/N, CEP: 14040-903, Ribeirão Preto, SP, Brazil.
authors.forename: Leandro Oliveira
authors.initials: LO
authors.lastname: Bortot
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, USP, Av. Café S/N, CEP: 14040-903, Ribeirão Preto, SP, Brazil.
authors.forename: João Francisco
authors.initials: JF
authors.lastname: Pereira
authors.affiliation: Instituto de Química-Unicamp, R. Josué de Castro s/n°, Cidade Universitária, CEP: 13083-861, Campinas, SP, Brazil.
authors.forename: Lauro Tatsuo
authors.initials: LT
authors.lastname: Kubota
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cummings
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, USP, Av. Café S/N, CEP: 14040-903, Ribeirão Preto, SP, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Dias-Baruffi
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, USP, Av. Café S/N, CEP: 14040-903, Ribeirão Preto, SP, Brazil.
authors.forename: Ivone
authors.initials: I
authors.lastname: Carvalho
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, USP, Av. Café S/N, CEP: 14040-903, Ribeirão Preto, SP, Brazil. Electronic address: vlcampo@fcfrp.usp.br.
authors.forename: Vanessa Leiria
authors.initials: VL
authors.lastname: Campo
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry*; D001386:Azides / Q000737:chemistry; D001798:Blood Proteins; D057930:Click Chemistry; D061565:Cycloaddition Reaction; D005697:Galactosides / Q000737:chemistry*; D037502:Galectin 3 / Q000737:chemistry*; D037161:Galectins; D006001:Glycoconjugates / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D007785:Lactose / Q000737:chemistry; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000480:Alkynes; D000596:Amino Acids; D001386:Azides; D001798:Blood Proteins; D005697:Galactosides; D037502:Galectin 3; D037161:Galectins; D006001:Glycoconjugates; C428445:LGALS3 protein, human; D008024:Ligands; D014230:Triazoles; D007785:Lactose
keywords: Galectin-3; Glycoconjugates; Molecular modeling; Surface plasmon resonance; Triazole; ‘Click chemistry’