Glyco-Conjugation of Thiosemicarbazone Copper(II) Complexes Enhances Selectivity toward Cancer Cells Overexpressing GLUT1

To overcome the limitations of conventional chemotherapy, specifically poor selectivity and systemic toxicity, this study explores a targeted approach leveraging the Warburg effect. We developed a series of novel copper(II) glucose-conjugated thiosemicarbazones (C1–C4), rationally designed to enhance water solubility and achieve good selectivity toward cancer cells. In vitro evaluations across a panel of human cancer cell lines demonstrated that free ligands were largely inactive, whereas copper(II) coordination significantly enhanced cytotoxicity. A strong linear correlation was observed between GLUT1 expression levels and cytotoxic potency, suggesting a possible involvement of GLUT-mediated uptake. Furthermore, when tested against HEK-293 cells, these complexes displayed a promising degree of selectivity, with selectivity indices (SI) up to four times higher than that of cisplatin. Mechanistic investigations indicated efficient intracellular accumulation together with inhibition of Protein Disulfide Isomerase (PDI). Morphological analysis via TEM and confocal microscopy in PSN-1 pancreatic cancer cells revealed features consistent with paraptosis rather than classical apoptosis. These findings suggest that metal-based glyco-conjugation is a highly effective strategy for developing selective, potent, and water-soluble anticancer agents capable of bypassing traditional drug resistance pathways.