Synthetic 1,2,3-triazole-linked glycoconjugates bind with high affinity to human galectin-3.
Bioorg Med Chem
; 23(13): 3414-25, 2015 Jul 01.
Article
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| MEDLINE
| ID: mdl-25975642
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Triazoles
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Glicoconjugados
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Galectina 3
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Galactósidos
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Aminoácidos
Límite:
Humans
Idioma:
En
Año:
2015
Tipo del documento:
Article