Biomolecular Interactions of Cytotoxic Ruthenium Compounds with Thiosemicarbazone or Benzothiazole Schiff Base Chelates

Herein we illustrate the formation and characterization of new paramagnetic ruthenium compounds, trans‐P‐[RuCl(PPh3)2(pmt)]Cl (1) (Hpmt=1‐((pyridin‐2‐yl)methylene)thiosemicarbazide), trans‐P‐[RuCl(PPh3)2(tmc)]Cl (2) (Htmc=1‐((thiophen‐2‐yl)methylene)thiosemicarbazide) and a diamagnetic ruthenium complex, cis‐Cl, trans‐P‐[RuCl2(PPh3)2(btm)] (3) (btm=2‐((5‐hydroxypentylimino)methyl)benzothiazole). Agarose gel electrophoresis experiments of the metal compounds illustrated dose‐dependent binding to gDNA by 1–3, while methylene blue competition assays suggested that 1 and 2 are also DNA intercalators. Assessment of the effects of the compounds on topoisomerase function indicated that 1–3 are capable of inhibiting topoisomerase I activity in terms of the ability to nick supercoiled plasmid DNA. The cytotoxic activities of the metal complexes were determined against a range of cancer cell lines versus a non‐tumorigenic control cell line, and the complexes were, in general, more cytotoxic towards the cancer cells, displaying IC50 values in the low micromolar range. Time‐dependent stability studies showed that in the presence of strong nucleophilic species (such as DMSO), the chloride co‐ligands of 1–3 are rapidly substituted by the former as proven by the suppression of the substitution reactions in the presence of an excess amount of chloride ions. The metal complexes are significantly stable in both DCM and an aqueous phosphate buffer containing 2 % DMSO. Thiosemicarbazone or benzothiazole Schiff base ruthenium compounds were found to display higher anticancer activities against HeLa cervical, HCC70 triple‐negative breast, and MCF‐7 hormone‐responsive breast cancer cells than against MCF‐12 A benign cells. DNA interaction studies showed that these octahedral metal complexes are partial DNA intercalators. These metal complexes illustrated optimal BSA uptake with preferential binding to BSA site I.