Journal Name RSCPublishing ARTICLE Cite this: DOI: 10.1039/x0xx00000x Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/ New palladium(II) and platinum(II) 5,5- diethylbarbiturate complexes with 2- phenylpyridine, 2,2’-bipyridine and 2,2’- dipyridylamine: synthesis, structures, DNA binding, molecular docking, cellular uptake, antioxidant activity and cytotoxicity Ceyda Icsel, a Veysel T. Yilmaz,* a Yunus Kaya, a Hale Samli, b William T. A. Harrison c and Orhan Buyukgungor d Novel palladium(II) and platinum(II) complexes of 5,5-diethylbarbiturate (barb) with 2-phenylpyridine (Hppy), 2,2’-bipyridine (bpy) and 2,2’-dipyridylamine (dpya) have been prepared and characterized by elemental analysis, IR, UV-Vis, NMR and ESI-MS. Single-crystal diffraction measurements show that complex 1 consists of binuclear [Pd2(µ-barb-κN,O)2(ppy-κN,C)2] moieties, while complexes 3–5 are mononuclear, [M(barb-κN)2(L-κN,N’)] (L = bpy or dpya). 6 has a composition of [Pt(dpya- κN,N’)2][Ag(barb-κN)2]2·4H2O and 2 was assumed to have a structure of [Pt(barb-κN)(Hppy-κN)(ppy- κN,C)]·3H2O. The complexes were found to exhibit significant DNA binding affinity by a non-covalent binding mode, in accordance with molecular docking studies. In addition, complexes 1 and 2 displayed strong binding with supercoiled pUC19 plasmid DNA. Cellular uptake studies were performed to assess the subcellular localization of the selected complexes. A moderate radical scavenging activity of 1 and 2 was confirmed by DPPH and ABTS tests. Complexes 1, 2, and 5 showed selectivity against HT-29 (colon) cell line. Introduction Since the discovery of anticancer activity of cisplatin, cis- [PtCl 2 (NH 3 ) 2 ], in the 1970’s, metal complexes have gained a progressively increasing interest in medicinal chemistry. 1-5 The more effective and less toxic second- and third-generation platinum-based anticancer agents, carboplatin and oxaliplatin with the leaving groups of 1,1-cyclobutanedicarboxylate and oxalate, respectively, were successfully tested and went on to achieve worldwide clinical acceptance. 6,7 The presence of chloride anions as leaving groups promotes DNA-binding ability of cisplatin via covalent bonding, while the carboxylate anions in carboplatin and oxaliplatin improve the water solubility and the stability of these complexes. 8-11 DNA is the main biological target for anticancer drugs. Hence, the design and synthesis of DNA targeting metal-based anticancer agents with potential cytotoxicity have gained importance in recent years. 12,13 Metal complexes containing aromatic ligands are reported to exhibit a dual-function mode of action, in which DNA binding occurs through both coordination with the metal centre, and non-covalent interaction such as intercalation with the DNA base pairs, along with π-π aromatic interactions between the double helix and the aromatic components of the metal complex. 14-18 Moreover, some metal complexes with bulky ligands are shown to act as DNA groove binders. 19-21 5,5-Diethylbarbituric acid (barbH), also known as barbitone, barbital, veronal or diemal, is a barbiturate derivative and is used as a sedative and hypnotic drug in the form of its soluble salt, sodium barbital. 22 The coordination chemistry of barbiturates is interesting and begins with the preparation of a crystalline copper(II) complex of 5,5-diethylbarbiturate (barb) with pyridine (py), [Cu(barb) 2 (py) 2 ]. 23 Barbituric acids are weak acids and readily deprotonate in aqueous solutions, forming corresponding barbiturate anions. The donor atoms such as amine N and carbonyl O atoms make the barbiturates interesting ligands, forming metal complexes from mononuclear species to coordination polymers and supramolecular assemblies. 24 Among barbiturates, metal This journal is © The Royal Society of Chemistry 2013 J. Name ., 2013, 00, 1-3 | 1