Journal of Medicinal Chemistry, 65, 5, 3866-3878 (2022)

15 března, 2022 9:57 am Published by Leave your thoughts

IF 7,446 

Glycopolymers Decorated with 3‑O-Substituted Thiodigalactosides as Potent Multivalent Inhibitors of Galectin‑3

Vrbata David, Filipová Marcela, Tavares R. Marina, Červený Jakub, Vlachová Miluše, Šírová Milada, Pelantová Helena, Petrásková Lucie, Bumba Ladislav, Konefal Rafal, Etrych Tomáš, Křen Vladimír, Chytil Petr, Bojarová Pavla


Galectin-3 (Gal-3) participates in many cancerrelated metabolic processes. The inhibition of overexpressed Gal-3 by, e.g., β-galactoside-derived inhibitors is hence promising for cancer treatment. The multivalent presentation of such inhibitors on a suitable biocompatible carrier can enhance the overall affinity to Gal-3 and favorably modify the interaction with Gal-3-overexpressing cells. We synthesized a library of C-3 aryl-substituted thiodigalactoside inhibitors and their multivalent N-(2-hydroxypropyl)methacrylamide (HPMA)-based counterparts with two different glycomimetic contents. Glycopolymers with a higher content of glycomimetic exhibited a higher affinity to Gal-3 as assessed by ELISA and biolayer interferometry. Among them, four candidates (with 4-acetophenyl, 4-cyanophenyl, 4-fluorophenyl, and thiophen-3-yl substitution) were selected for further evaluation in cancer-related experiments in cell cultures. These glycopolymers inhibited Gal-3-induced processes in cancer cells. The cyanophenyl-substituted glycopolymer exhibited the strongest antiproliferative, antimigratory, antiangiogenic, and immunoprotective properties. The prepared glycopolymers appear to be prospective modulators of the tumor microenvironment applicable in the therapy of Gal-3-associated cancers.

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