The binding of human galectins by glycomimetic inhibitors is a promising therapeutic approach. The structurally distinct group of tandem-repeat galectins has scarcely been studied so far, and there is hardly any knowledge on their ligand specificity or their inhibitory potential, particularly concerning non-natural carbohydrates. Here, we present the synthesis of a library of seven 3--disubstituted thiodigalactoside-derived glycomimetics and their affinity to two tandem-repeat galectins, Gal-8 and Gal-9. The straightforward synthesis of these glycomimetics involved dibutyltin oxide-catalyzed 3,3́--disubstitution of commercially available unprotected thiodigalactoside, and conjugation of various aryl substituents by copper-catalyzed Huisgen azide-alkyne cycloaddition (CuAAC). The inhibitory potential of the prepared glycomimetics for Gal-8 and Gal-9 was assessed, and compared with the established galectins Gal-1 and Gal-3. The introduction of C-3 substituents resulted in an over 40-fold increase in affinity compared with unmodified TDG. The structure-affinity relations within the studied series were discussed using molecular modeling. Furthermore, the prepared glycomimetics were shown to scavenge Gal-8 and Gal-9 from the surface of cancer cells. This pioneering study on the synthetic inhibitors especially of Gal-9 identified lead compounds that may be used in further biomedical research.

中文翻译：

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串联重复半乳糖凝集素的糖基模拟抑制剂：简单而有效

糖模拟抑制剂与人半乳糖凝集素的结合是一种有前途的治疗方法。迄今为止，结构上不同的串联重复半乳糖凝集素几乎没有被研究过，并且几乎没有关于它们的配体特异性或它们的抑制潜力的任何知识，特别是关于非天然碳水化合物。在这里，我们展示了七种 3-二取代硫代二半乳糖苷衍生的糖模拟物文库的合成及其对两种串联重复半乳糖凝集素 Gal-8 和 Gal-9 的亲和力。这些糖模拟物的直接合成涉及二丁基氧化锡催化的市售未保护的硫代二半乳糖苷的 3,3́-二取代，以及通过铜催化的 Huisgen 叠氮化物-炔环加成 (CuAAC) 进行的各种芳基取代基的缀合。评估了制备的糖模拟物对 Gal-8 和 Gal-9 的抑制潜力，并与已建立的半乳糖凝集素 Gal-1 和 Gal-3 进行了比较。与未修饰的 TDG 相比，C-3 取代基的引入导致亲和力增加了 40 倍以上。使用分子模型讨论了所研究系列中的结构亲和关系。此外，制备的糖模拟物被证明可以清除癌细胞表面的 Gal-8 和 Gal-9。这项针对合成抑制剂（尤其是 Gal-9）的开创性研究确定了可用于进一步生物医学研究的先导化合物。