Steric and Electronic Effects of N‐(2‐Picolyl)salicylimine Ligands on the Anticancer Activity of Pt(II) Complexes

A series of platinum(II) complexes incorporating tridentate Schiff base ligands with diverse steric and electronic properties was investigated to elucidate structure–property–activity relationships. Spectroscopic characterization, NBO analyses, and solubility measurements reveal that electronic effect play a more significant role than steric factors in determining spectroscopic behavior, solubility, lipophilicity, and biomolecular interactions. Among the series, Pt1 bearing the ethoxy substituent exhibits enhanced DMSO solubility, resulting in the strongest biomolecule binding and the highest cytotoxicity activity. The methoxy group at the 4‐position in Pt3 provides a moderate enhancement through favorable resonance effects ( para to azomethine moiety). In contrast, methoxy substitution at other positions ( Pt2 and Pt4 ) or increased steric bulkiness ( Pt5 ), negatively affects biomolecular interactions. All complexes interact with DNA through intercalative binding and form adducts with BSA. In vitro cytotoxicity against MCF‐7 and HCT‐116 cell lines correlates with both solubility and biomolecular affinity, with Pt1 approaching the potency of cisplatin (IC 50 ≈ 25 µM). Cell‐cycle and apoptosis analyses indicate only mild S‐phase arrest and apoptosis, suggesting a mechanism distinct from that of cisplatin, which acts primarily through DNA cross‐linking and subsequent DNA damage. These findings identify Pt1 as a promising compound and demonstrate that rational tuning of ligand electronics and structural flexibility offers an effective strategy for tuning the biological performance of Pt(II) anticancer scaffolds with potentially reduced genotoxicity.