Dalton Transactions PAPER Cite this: Dalton Trans., 2014, 43, 1203 Received 20th June 2013, Accepted 8th October 2013 DOI: 10.1039/c3dt51641e www.rsc.org/dalton New ruthenium(II) arene complexes of anthracenyl- appended diazacycloalkanes: effect of ligand intercalation and hydrophobicity on DNA and protein binding and cleavage and cytotoxicity† Mani Ganeshpandian, a Rangasamy Loganathan, a Eringathodi Suresh, b Anvarbatcha Riyasdeen, c Mohammad Abdulkadher Akbarsha d,e and Mallayan Palaniandavar* a A series of half-sandwich Ru(II ) arene complexes of the type [Ru(η 6 -arene)(L)Cl](PF 6 ) 1–4, where arene is benzene (1, 2) or p-cymene (3, 4) and L is N-methylhomopiperazine ( L1) or 1-(anthracen-10-ylmethyl)-4-methylhomopipera- zine (L2), has been isolated and characterized by using spectral methods. The X-ray crystal structures of 2, 3 and 4 reveal that the compounds possess a pseudo-octahedral “piano-stool ” structure equipped with the arene ligand as the seat and the bidentate ligand and the chloride ion as the legs of the stool. The DNA binding affinity determined using absorption spectral titrations with CT DNA and competitive DNA binding studies varies as 4 > 2 > 3 > 1, depending upon both the arene and diazacycloalkane ligands. Complexes 2 and 4 with higher DNA binding affinities show strong hypochromism (56%) and a large red-shift (2, 10; 4, 11 nm), which reveals that the anthracenyl moiety of the ligand is stacked into the DNA base pairs and that the arene ligand hydrophobicity also dictates the DNA binding affinity. In contrast, the monocationic complexes 1 and 3 are involved in electrostatic binding in the minor groove of DNA. The enhancement in viscosities of CT DNA upon binding to 2 and 4 are higher than those for 1 and 3 support- ing the DNA binding modes of interaction inferred. All the complexes cleave DNA effectively even in the absence of an external agent and the cleavage ability is enhanced in the presence of an activator like H 2 O 2 . Tryptophan quench- ing measurements suggest that the protein binding affinity of the complexes varies as 4 > 2 > 3 > 1, which is the same as that for DNA binding and that the fluorescence quenching of BSA occurs through a static mechanism. The positive ΔH 0 and ΔS 0 values for BSA binding of complexes indicate that the interaction between the complexes and BSA is mainly hydrophobic in nature and the energy transfer efficiency has been analysed according to the Förster non-radiative energy transfer theory. The variation in the ability of complexes to cleave BSA in the presence of H 2 O 2 , namely, 4 > 2 > 3 > 1, as revealed from SDS-PAGE is consistent with their strong hydrophobic interaction with the protein. The IC 50 values of 1–4 (IC 50 : 1, 28.1; 2, 23.1; 3, 26.2; 4, 16.8 μM at 24 h; IC 50 : 1, 19.0; 2, 15.9; 3, 18.1; 4, 9.7 μM at 48 h) obtained for MCF 7 breast cancer cells indicate that they have the potency to kill cancer cells in a time dependent manner, which is similar to cisplatin. The anticancer activity of complexes has been studied by employing various biochemical methods involving different staining agents, AO/EB and Hoechst 33258, which reveal that complexes 1–4 establish a speci fic mode of cell death in MCF 7 breast cancer cells. The comet assay has been employed to determine the extent of DNA fragmentation in cancer cells. Introduction The most successful platinum-based anticancer drugs like cis- platin and other multi-nuclear platinum compounds are useful in the treatment of testicular and ovarian cancers and are also widely employed for treating bladder, cervical, head and neck, oesophageal and small cell lung cancers. 1 However, they show several side effects including nephrotoxicity, emetogenesis and neurotoxicity during treatment of cancer 2 and the activity is limited by both toxicity and acquired resistance. 3 The two Ru(III) complexes KP 1019 (indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)]) and NAMI-A † Electronic supplementary information (ESI) available. CCDC 927197–927199 and 961677. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3dt51641e a Department of Chemistry, Central University of Tamil Nadu, Thiruvarur 610 004, India b Analytical Department and Centralized Instrument Facility, Central Salt and Marine Chemical Research Institute, Council of Scientific and Industrial Research (CSIR-CSMCRI), Bhavnagar 364 002, India c Department of Animal Science, Bharathidasan University, Tiruchirappalli – 620 024, Tamilnadu, India d Mahatma Gandhi-Doerenkamp Center for Alternatives to Use of Animals in Life Science Education, Bharathidasan University, Tiruchirappalli, 620024 Tamilnadu, India e Department of Food and Nutrition, King Saud University, Riyadh, Kingdom of Saudi Arabia. E-mail: palaniandavar@cutn.ac.in, palanim51@yahoo.com This journal is © The Royal Society of Chemistry 2014 Dalton Trans. , 2014, 43, 1203–1219 | 1203 Published on 09 October 2013. Downloaded by Bharatidasan University on 25/09/2014 11:21:02. 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