Organometallic ruthenium(II) scorpionate as topo IIα inhibitor; in vitro binding studies with DNA, HPLC analysis and its anticancer activity

• Novel (η6-arene)Ru(II) (carboxyphenyl)bis(pyrazolyl)methane derivatives have been prepared.
• DNA binding studies.
• Ability to significantly cleave pBR322 DNA.
• Topo IIα isomerase inhibitory activity.
• η6-arene capped Ru(II) complexes show moderate cytotoxicity.

New organoruthenium [(η6-arene)RuII(L)Cl]Cl (1: arene = p-cymene, L = L1; 2: arene = p-cymene, L = L2; 3: arene = benzene, L = L1; 4: arene = benzene; L = L2; L1 = bis(3,5-dimethylpyrazolyl)parabenzoic acid, L2 = bis(3,5-dimethylpyrazolyl)metabenzoic acid) have been synthesized and characterized by analytical and spectroscopic methods. The molecular structure of [(η6-p-cymene)RuCl(L1)]Cl (1) was determined by single crystal X-ray diffraction studies. Preliminary in vitro binding studies of 1–4 with CT DNA were carried out by employing various biophysical techniques which revealed their avid DNA binding via non-covalent binding mode viz; partial intercalation of the η6-arene group as well as electrostatic surface interaction through one oxygen atom of the phosphate backbone of the DNA helix; however, complexes 1 and 3 display higher binding propensity in comparison to 2 and 4, as quantified by Kb. The interaction was further analysed by HPLC technique. The results of the cleavage experiments of pBR322 DNA with 1 and 3 displayed significantly good cleavage at 20–40 μM, following the oxidative pathway. These findings have revealed that the hydrophobic arene, and the chloride leaving group have important roles in the novel mechanism of recognition of DNA by (η6-arene)ruthenium(II) complexes, and will aid the design of more effective anticancer complexes, as well as new site-specific DNA reagents. Furthermore, the anticancer activity of the complexes 1 and 3 on 15 cell lines of different histological origin has been studied. It has been observed that 1 exhibits higher cytotoxicity than 3, and the cells undergo apoptotic cell death.

The new four η6-arene capped ruthenium(II) complexes 1–4, have been synthesized from the dinuclear precursors [(η6-arene)RuCl2]2 (arene = para-cymeme or benzene) and the corresponding (carboxyphenyl)bis(pyrazolyl)methane ligands, L1 and L2. These complexes 1–4 were studied for DNA binding, DNA cleavage, topo IIα inhibition and cytotoxicity.Figure optionsDownload as PowerPoint slide