Ferrocene- and ruthenium arene-containing glycomimetics as selective inhibitors of human galectin-1 and -3

Galectins are a family of β-galactoside-binding proteins whose dysregulation is associated with various physiological and pathological processes, including fibrotic disorders, inflammation, and cancer. Elevated expression of galectin-1 promotes tumor cell migration and immune evasion, while galectin-3 is linked to increased tumor invasiveness and metastasis formation. Pharmacological inhibition of galectins, therefore, represents a promising therapeutic strategy.

In this study, we synthesized a novel series of galectin inhibitors incorporating ferrocene and organoruthenium sandwich complexes attached to lactose, N-acetyllactosamine, or thiodigalactoside scaffolds. The binding affinities of these compounds to human galectin-1 (hgal-1) and galectin-3 (hgal-3) were evaluated using fluorescence polarization, intrinsic fluorescence of galectin tryptophan residues, and isothermal titration calorimetry.

A symmetrical diferrocene thiodigalactoside emerged as one of the most potent known inhibitors of hgal-1, exhibiting nanomolar affinity and up to 50-fold selectivity for hgal-1 over hgal-3. In contrast, asymmetrical monoferrocenyl thiodigalactosides demonstrated nanomolar affinities for both galectins. Additionally, the presence of the ferrocene motif enables these inhibitors to serve as electrochemical probes in follow-up studies. NMR analyses and molecular modeling suggest that the steric bulk of the ferrocene motif restricts binding modes for hgal-3, leading to unexpected selectivity for hgal-1.

This research was conducted in collaboration between the Research Group of Bioorganic Chemistry and Biomaterials at the Institute of Chemical Process Fundamentals, the Institute of Organic Chemistry and Biochemistry, the Institute of Biophysical Chemistry, and the Masaryk Memorial Cancer Institute. The findings open new avenues for designing galectin inhibitors with therapeutic potential in oncology.

• Hamala V., Kurfiřt M., Červenková Šťastná L., Hujerová H., Bernášková J., Parkan K., Kaminský J., Habanová N., Kozák J., Magdolenová A., Zavřel M., Staroňová T., Ostatná V., Žaloudková L., Daňhel A., Holčáková J., Voňka P., Hrstka R.*, Karban J.*: Ferrocene-and ruthenium arene-containing glycomimetics as selective inhibitors of human galectin-1 and -3. Inorganic Chemistry Frontiers 2024, 11, 7588–7609. doi.org/10.1039/D4QI01555J