Marchiori Marcelo Fiori, Souto Dênio Emanuel Pires, Bortot Leandro Oliveira, Pereira João Francisco, Kubota Lauro Tatsuo, Cummings Richard D, Dias-Baruffi Marcelo, Carvalho Ivone, Campo Vanessa Leiria
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, USP, Av. Café S/N, CEP: 14040-903, Ribeirão Preto, SP, Brazil.
Instituto de Química-Unicamp, R. Josué de Castro s/n°, Cidade Universitária, CEP: 13083-861, Campinas, SP, Brazil.
Bioorg Med Chem. 2015 Jul 1;23(13):3414-25. doi: 10.1016/j.bmc.2015.04.044. Epub 2015 Apr 28.
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.
本研究描述了1,2,3 - 三唑氨基酸衍生的3 - O - 半乳糖苷1 - 6和1,2,3 - 三唑二乳糖衍生的糖缀合物7的合成，它们是潜在的半乳糖凝集素 - 3抑制剂。目标化合物通过叠氮基衍生的氨基酸N3 - ThrOBn、N3 - PheOBn、N3 - N - Boc - TrpOBn、N3 - N - Boc - LysOBn、N3 - O - tBu - AspOBn和N3 - l - TyrOH与相应的基于炔烃的糖3 - O - 丙炔基 - GalOMe之间的铜（I）催化的叠氮化物 - 炔烃环加成反应（“点击化学”）合成，以及通过叠氮基乳糖与2 - 丙炔基乳糖之间的点击化学反应合成。表面等离子体共振（SPR）分析表明，所有合成的糖缀合物1 - 7都以高亲和力与半乳糖凝集素 - 3结合，但结合力最强的是氨基酸衍生的糖缀合物2（KD 7.96μM）和4（KD 4.56μM），以及二价乳糖苷7（KD1 0.15μM/KD2 19μM）。分子模拟结果与SPR分析一致，因为糖缀合物2、4和7与半乳糖凝集素 - 3的相互作用更稳定。对于化合物2和4，它们建立了特定的阳离子 - π（Arg144）和离子（Asp148）相互作用，而糖缀合物7能够桥接两个独立的半乳糖凝集素 - 3 CRD，在两个单体之间形成非共价交联，从而对半乳糖凝集素 - 3具有亚微摩尔亲和力。
