Modulating Cytotoxicity in HeLa Cells via Aromatic Ring Variation in Cu(I) Complexes

The persistent global burden of cancer underscores the need for alternative therapeutic strategies beyond conventional chemotherapeutics, with metal-based agents offering distinct advantages due to their structural tunability and diverse biological modes of action. In this work, a series of thiosemicarbazone ligands bearing a progressively increasing number of aromatic rings were synthesized and employed to generate four Cu(I) complexes (1-4). Comprehensive characterization by spectroscopic techniques and single-crystal X-ray diffraction confirmed distorted tetrahedral geometries with bidentate N, S-coordination and stabilization by triphenylphosphine co-ligands. The cytotoxic potential of the ligands and complexes was evaluated against human cervical cancer (HeLa) cells using multiple in vitro assays. A clear structure-activity relationship was observed, wherein cytotoxic efficacy increased with aromatic ring density, with complex 4 exhibiting the strongest antiproliferative activity. Biochemical analyses revealed reduced glucose uptake, suppressed cell proliferation, and enhanced lactate dehydrogenase release. Apoptosis induction was validated by DAPI staining and Annexin V-FITC/PI flow cytometry, while in ovo chorioallantoic membrane assays demonstrated significant inhibition of neovascularization. Overall, these results establish ligand aromaticity as a key factor governing anticancer activity, providing insight into structure-activity correlations and highlighting the potential of Cu(I) complexes as promising candidates for further anticancer therapeutic development.