Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides’ fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (K_d down to 1–2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (K_d 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor–galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization and a competitive ligand optimal for analyzing high affinity galectin-3 inhibitors with competitive isothermal titration calorimetry.

中文翻译：

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氟-半乳糖凝集素3相互作用的系统调优提供了具有单数字nM亲和力和高选择性的硫金杜糖苷衍生物

已经合成了对称和不对称的氟化苯基三唑基-硫代双糖苷衍生物，并被评估为半乳糖凝集素-1和半乳糖凝集素-3的抑制剂。系统性地调节苯基三唑基-硫代二乳糖苷与半乳凝素3的氟相互作用，从而发现了在对称取代的硫代二乳糖苷中具有优异亲和力（K _d降至1-2 nM）的抑制剂，以及无与伦比的高亲和力组合（K _d通过携带一个三氟苯基三唑和一个香豆基部分，对不对称硫代二糖半乳糖苷的选择性为7.5 nM），相对于半乳凝素1的选择性（46倍）。抑制剂-半乳凝素复合物的等温滴定热分析和X射线晶体学研究表明，氟酰胺相互作用对于亲和力和选择性很重要。最后，发现的抑制剂的高亲和力需要开发两种竞争性滴定测定工具：一种用于竞争性荧光偏振的新型高亲和力荧光探针，以及一种通过竞争性等温滴定量热法分析高亲和性Galectin-3抑制剂的最优竞争性配体。