Original article In vitro cytotoxicity studies of palladacyclic complexes containing the symmetric diphosphine bridging ligand. Studies of their interactions with DNA and BSA Kazem Karami a, * , Mahboubeh Hosseini-Kharat a , Hojjat Sadeghi-Aliabadi b , Janusz Lipkowski c , Mina Mirian d a Department of Chemistry, Isfahan University of Technology, Isfahan 84156/83111, Iran b Department of Pharmaceutical Chemistry, Isfahan University of Medical Sciences, Isfahan, Iran c Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland d Department of Molecular Medicine, Isfahan University of Medical Sciences, Isfahan, Iran article info Article history: Received 16 October 2013 Received in revised form 18 November 2013 Accepted 24 November 2013 Available online 12 December 2013 Keywords: Palladacyclic complex FS-DNA binding BSA binding Cytotoxicity Crystal structure abstract The reactions between [Pd 2 {(C,N)eC 6 H 4 CH 2 NH(Et)} 2 (m-X) 2 ] (X ¼ Cl or Br) and 1,2- bis(diphenylphosphino)ethane (dppe) in the 1:1 molar ratio resulted in the dppe-bridged Pd(II) com- plexes, [Pd 2 {(C,N)eC 6 H 4 CH 2 NH(Et)} 2 (m-dppe)(Cl) 2 ](1) and [Pd 2 {(C,N)eC 6 H 4 CH 2 NH(Et)} 2 (m-dppe)(Br) 2 ] (2), respectively, which were characterized by elemental analyses, infrared (IR), 1 H- and 31 P{ 1 H} NMR spectroscopy. The molecular structure of 1 was determined by single-crystal X-ray diffraction. In vitro cytotoxicity of 1 , 2, dppe, PhCH 2 NH(Et) and cisplatin were carried out against four human tumor cell lines. The interactions of complexes towards DNA and protein are investigated. The results suggested that both complexes could interact with FS-DNA through the intercalation mode. Moreover, the reactivity towards BSA revealed that the microenvironment and the secondary structure of BSA were changed in the presence of Pd(II) complexes. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction To date, cisplatin and its analogs are some of the most effective chemotherapeutic agents in clinical use as the first line of treat- ment in testicular and ovarian cancers [1e6]. Furthermore, these analogs are increasingly used against other tumors, such as cervical, bladder and head/neck tumors. Unfortunately, they have several major side effects. Cumulative toxicities of nephrotoxicity, ototox- icity and tumor resistance related to them have stimulated the search for other antitumor-active metal complexes with improved pharmacological properties [7e12]. Mechanistic investigations of the mechanism of action of Pt(II) anticancer drugs, represent that their Pd(II) analogs are suitable model compounds since they exhibit ca. 10 4 e10 5 times higher reactivity, whereas their structural and equilibrium behavior are very similar [13]. Among palladium(II) complexes, special attention has been paid to metallacycle complexes with nitrogen donor li- gands, such as various alkyl and aryl substituted amines and imines, azo, hydrazo and heterocyclic compounds. The chelate ring gener- ally possesses three to seven members, with the five-membered ring being most favored. These compounds are used successfully in organic synthesis [14e16], homogeneous and heterogeneous catalysis [17e19], asymmetric synthesis [20], photochemistry [21], optical resolution [22,23], and are rather promising as liquid crys- tals [24,25] and potential biologically active materials [26e30]. In the development of new such metal-based therapeutics, detailed studies on the interactions between DNA and transition- metal complexes is needed [31]. Depending on the exact nature of the metal and ligand, the complexes can bind with nucleic acid covalently or non-covalently [32,33]. Non-covalent interactions between transition-metal complexes and DNA can occur by inter- calation, groove binding, or external electrostatic binding. There- fore, the study on the interaction of the transition metal complexes with DNA is of great significance for the design of new drugs and their application. It has been found that some ortho-metalated species may bind to DNA by means of intercalative or monofunctional covalent * Corresponding author. Tel.: þ98 3113913239; fax: þ98 3113912350. E-mail addresses: karami@cc.iut.ac.ir (K. Karami), m.hosseinikharat@ch.iut.ac.ir (M. Hosseini-Kharat). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2013.11.042 European Journal of Medicinal Chemistry 73 (2014) 8e17