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

0556381 - MBÚ 2023 RIV US eng J - Journal Article
Vrbata, David - Filipová, Marcela - Tavares, Marina Rodrigues - Červený, Jakub - Vlachová, Miluše - Šírová, Milada - Pelantová, Helena - Petrásková, Lucie - Bumba, Ladislav - Konefal, Rafal - Etrych, Tomáš - Křen, Vladimír - Chytil, Petr - Bojarová, Pavla
Glycopolymers Decorated with 3-O-Substituted Thiodigalactosides as Potent Multivalent Inhibitors of Galectin-3.
Journal of Medicinal Chemistry. Roč. 65, č. 5 (2022), s. 3866-3878. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT(CZ) LTC19038; GA ČR(CZ) GA22-00262S; GA MZd(CZ) NU21-03-00273
EU Projects: European Commission(XE) CA17140 - COST Action
Institutional support: RVO:61388971 ; RVO:61389013
Keywords : digit nm affinity * high selectivity * click chemistry * copolymers * glycopeptide * recognition * derivatives * apoptosis * fibrosis * arginine
OECD category: Biochemistry and molecular biology; Polymer science (UMCH-V)
Impact factor: 7.3, year: 2022
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01625

Galectin-3 (Gal-3) participates in many cancer-related metabolic processes. The inhibition of overexpressed Gal-3 by, e.g., beta-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-over-expressing 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.
Permanent Link: http://hdl.handle.net/11104/0330739