In medio stat virtus: asymmetric Salphen metal complexes with improved biological properties

We have synthesized and characterized three Zn(ii) Salphen complexes with different ligand modifications to evaluate their biological properties in terms of DNA binding, cellular uptake and anticancer activity. Particular attention was given to the synthesis of an asymmetric Salphen complex using mechanochemistry to prevent unwanted side products. The symmetric neutral complex bearing lateral chlorine substituents showed low aqueous solubility, no detectable binding to G-quadruplex (G4) DNA, yet good cytotoxicity. In contrast, the symmetric dicationic derivative exhibited effective G4 stabilization only at high concentrations but lacked cellular activity. Notably, the asymmetric monocationic complex, combining both substituents, achieved a more favorable balance of properties, displaying improved water solubility relative to the neutral analogue, enhanced membrane permeation, and retained cytotoxicity against pancreatic cancer cells. Cellular uptake studies confirmed its efficient internalization via passive transport, and fluorescence microscopy revealed cytoplasmic accumulation. Notably, the asymmetric complex significantly reduced cancer cell viability, inhibited proliferation, and induced apoptotic cell death, as evidenced by PARP cleavage. These findings underscore the potential of asymmetric Salphen complexes as promising anticancer agents and provide valuable insights for the rational design of metal-based therapeutics based on the Salphen scaffold.