Dalton Transactions Dynamic Article Links Cite this: Dalton Trans., 2012, 41, 2066 www.rsc.org/dalton PAPER Ruthenium(II)/(III) complexes of 4-hydroxy-pyridine-2,6-dicarboxylic acid with PPh 3 /AsPh 3 as co-ligand: Impact of oxidation state and co-ligands on anticancer activity in vitro† Thangavel Sathiya Kamatchi, a Nataraj Chitrapriya, b Hyosun Lee,* b Chris F. Fronczek, c Frank R. Fronczek c and Karuppannan Natarajan* a Received 5th July 2011, Accepted 31st October 2011 DOI: 10.1039/c1dt11273b With the aim to develop more efficient, less toxic, target specific metal drugs and evaluate their anticancer properties in terms of oxidation state and co-ligand sphere, a sequence of Ru II , Ru III complexes bearing 4-hydroxy-pyridine-2,6-dicarboxylic acid and PPh 3 /AsPh 3 were synthesized and structurally characterized. Biological studies such as DNA binding, antioxidant assays and cytotoxic activity were carried out and their anticancer activities were evaluated. Interactions of the complexes with calf thymus DNA revealed that the triphenylphosphine complexes could bind more strongly than the triphenylarsine complexes. The free radical scavenging ability, assessed by a series of in vitro antioxidant assays involving DPPH radical, hydroxyl radical, nitric oxide radical, superoxide anion radical, hydrogen peroxide and metal chelating assay, showed that the Ru III complexes possess excellent radical scavenging properties compared to those of Ru II . Cytotoxicity studies using three cancer lines viz HeLa, HepG2, HEp-2 and a normal cell line NIH 3T3 showed that Ru II complexes exhibited substantial cytotoxic specificity towards cancer cells. Furthermore, the Ru II complexes were found to be superior to Ru III complexes in inhibiting the growth of cancer cells. Introduction Metal complexes offer infinite opportunities for the design of compounds with bioactivity due to the large variety of available metals and the ability to tune the reactivity and structure of the metal complexes by their ligand spheres. 1 In general, the nature of the metal ion, its oxidation state, the types and number of bound a Department of Chemistry, Bharathiar University, Coimbatore, 641046, India. E-mail: k_natraj6@yahoo.com; Fax: +91-422-2422387; Tel: +91- 422-2428319 b Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, 1370 Sankyuk-dong, Buk-gu, Deagu, 702- 701, Republic of Korea. E-mail: hyosunlee@knu.ac.kr; Fax: +82-53-950- 6330; Tel: +82-53-950-5337 c Department of Chemistry, Louisiana State University, Baton Rouge, LA, 70803, USA †Electronic supplementary information (ESI) available: 1 H NMR spec- trum of the complex [Ru II -hpa-P] (Fig. S1). Cyclic voltammetric response of [Ru II -hpa-P] (Fig. S2). X-Ray crystal structure and atom numbering scheme for [Ru III -hpa-As] (Fig. S3). Hydrogen-bonding distances and angles (Table S1). Plot of (e a -e f )/(e b -e f ) vs. [DNA] for the titration of DNA with complexes. Emission spectra of EB bound to DNA in the absence and presence of [Ru III -hpa-P]. Stern–Volmer quenching plot of EB bound to CT-DNA by ruthenium complexes (Fig. S4–S6). Antioxidant activity of all the complexes against various radicals (Fig. S7). Concentration effect curves of the complexes against HeLa, HepG2, HEp-2 and NIH 3T3 cell lines (Fig. S8–S11). CCDC reference numbers 797111–797113. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1dt11273b ligands and isomers of the complex can all exert a critical influence on the biological activity of a metal complex. 2–4 An understanding of how these factors affect biological activity should enable the design of metal complexes with specific medicinal properties. The wide spectrum of contrasting biological activity amongst platinum complexes 5–7 and the clinical success of Pt II diam(m)ine complexes, e.g. cisplatin, as anticancer drugs provide a good illustration of this point. Although 70% of all cancer patients receive cisplatin during cancer treatment, chemotherapy with cisplatin and its analogues still has several drawbacks; toxic side-effects and lack of activity (drug resistance) against several types of cancer are problems which need to be overcome. 8 This provides the impetus for the search for anticancer activity amongst complexes of other metals. At this juncture, ruthenium, a rare transition metal of the platinum group, has emerged as an attractive alternative due to several favorable properties suited to rational anticancer drug design and biological applications. Biologically compatible ligand-exchange kinetics of Ru II and Ru III similar to those of platinum complexes, a higher coordination number that could potentially be used to fine-tune the properties of the complexes, and lower toxicity (than their platinum counterparts) towards healthy tissues by mimicking iron in binding to many biological molecules are the advantages of using ruthenium complexes. 9,10 The entrance of two Ru III based drugs, NAMI-A 11 and KP1019 12 (Fig. 1) into clinical trials for the treatment of metastatic tumors 2066 | Dalton Trans., 2012, 41, 2066–2077 This journal is © The Royal Society of Chemistry 2012 Downloaded by Yeungnam University on 20 February 2013 Published on 20 December 2011 on http://pubs.rsc.org | doi:10.1039/C1DT11273B View Article Online / Journal Homepage / Table of Contents for this issue