Development of new glycosyl-chalcones targeting cancer cells through recognition of cellular carbohydrate receptors

Aims Despite advances in cancer therapy, tumor aggressiveness remains a challenge due to rapid progression and genetic variability. Tumor cells often overexpress glucose transporters (GLUTs) and receptors such as galectin and ASGP-R. Based on this, new chalcone derivatives conjugated to D-glucose, D-galactose, and lactose were synthesized from a previously identified cytotoxic chalcone (compound 1) to evaluate their anticancer potential.Materials and methods The compounds were synthesized as O-glycosides or glycosyl-1,2,3-triazole chalcones and tested against cancer and normal cell lines. Cellular assays assessed cytotoxicity, colony formation, migration, morphology, cell cycle progression, and apoptosis. Molecular docking and dynamics simulations investigated interactions with MMP-9, a key enzyme in metastasis.Results O-galactosyl chalcone 9 showed the most promising activity, surpassing compound 1 against HeLa (CC50 4.58 µM) and T-24 (CC50 4.41 µM) cells, with improved selectivity over doxorubicin. Chalcone 9 inhibited colony formation and migration, induced morphological changes, modulated the cell cycle, and triggered apoptosis in HepG2 and T-24 cells via p53-dependent and independent mechanisms. Molecular modeling has revealed stable interactions between the galactosyl moiety and MMP-9, supporting its role as a potential target.Conclusions Chalcone 9 exhibits potent, selective anticancer activity and anti-migratory effects, representing a promising candidate for further drug development.