Ruthenium(II)–arene complexes of diimines: Effect of diimine intercalation and hydrophobicity on DNA and protein binding and cytotoxicity

Abstract

A series of half‐sandwich Ru(II)–arene complexes [Ru(η6‐benzene)(diimine)Cl](PF6) (1–4), where diimine is 1,10‐phenanthroline (1), 5,6‐dimethyl‐1,10‐phenanthroline (2), dipyrido[3,2‐a:2′,3′‐c]phenazine (3) or 11,12‐dimethyldipyrido[3,2‐a:2′,3′‐c]phenazine (4), have been isolated and characterized using analytical and spectral methods. Complex 2 possesses a familiar pseudo‐octahedral ‘piano‐stool’ structure. The intrinsic DNA binding affinity of the complexes depends upon the diimine ligand: 3 (dppz) > 4 (11,12‐dmdppz) > 2 (5,6‐dmp) > 1 (phen). The π‐stacking interaction of extended planar ring of coordinated dppz (3) in between the DNA base pairs is more intimate than that of phen (1), and the incorporation of methyl groups on the dppz ring (4) discourages the stacking interaction leading to a lower DNA binding affinity for 4 than 3. Docking studies show that all the complexes bind in the major groove of DNA. Interestingly, 3 shows an ability to convert supercoiled DNA into nicked circular DNA even at 20 μM concentration beyond which complete oxidative DNA degradation is observed. The protein binding affinity of the complexes decreases in the order 4 > 3 > 2 > 1, and the higher protein binding affinity of 4 illustrates the strong involvement of methyl groups on dppz ring in hydrophobic interaction with protein. Also, 4 cleaves protein more efficiently than the other complexes in the presence of H2O2. It is notable that 2, 3 and 4 display cytotoxicity against human cervical cancer cell lines (SiHa) with potency higher than the currently used drug cisplatin. Acridine orange/ethidium bromide staining studies reveal that 3 induces apoptosis in cancer cells much more efficiently than 4.