Van't Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands.
Angew Chem Int Ed Engl. 2021 Jul 12;60(29):16178-16183. doi: 10.1002/anie.202104924. Epub 2021 Jun 15.
Galectins are a galactoside specific subclass of carbohydrate binding proteins (lectins) involved in various cellular activities, certain cancers, infections, inflammations, and many other biological processes. The molecular basis for the selectivity of galectins is well-documented and revolves around appropriate interaction complementarity: an aromatic residue for C-H⋅⋅⋅π interactions and polar residues for (charge assisted) hydrogen bonds with the axial hydroxyl group of a galactoside. However, no synthetic mimics are currently available. We now report on the design and synthesis of the first galectin mimic (6), and show that it has a higher than 65-fold preference for n-octyl-β-galactoside (8) over n-octyl-β-glucoside (7) in CD Cl containing 5 % [D ]DMSO (with K ≥4500 M for 6:8). Molecular modeling informed by nOe studies reveal a high degree of interaction complementarity between 6 and galactoside 8, which is very similar to the interaction complementarity found in natural galectins.
半乳糖凝集素是一类半乳糖特异性的糖结合蛋白（凝集素），参与多种细胞活动、某些癌症、感染、炎症以及许多其他生物学过程。半乳糖凝集素选择性的分子基础已有充分的文献记载，主要围绕着适当的相互作用互补性：一个芳基残基用于 C-H···π 相互作用，极性残基用于与半乳糖苷的轴向羟基形成（电荷辅助）氢键。然而，目前还没有合成模拟物。我们现在报告了第一个半乳糖凝集素模拟物（6）的设计和合成，并表明它在含有 5%[D ]DMSO 的 CDCl 3中对半乳糖基辛基-β-糖苷（8）的偏好度高于对葡萄糖基辛基-β-糖苷（7）（6:8 的 K 值≥4500 M）。基于 NOE 研究的分子建模揭示了 6 与半乳糖苷 8 之间具有高度的相互作用互补性，这与天然半乳糖凝集素中发现的相互作用互补性非常相似。
