e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 7 ( 2 0 1 4 ) 897–906 Available online at www.sciencedirect.com ScienceDirect jo ur nal homepage: www.elsevier.com/locate/etap Investigation of the pharmacological profiles of dinuclear metal complexes as novel, potent and selective cytotoxic agents against ras-transformed cells R. Beklem Bostancıo ˘ glu a,∗ , A. Tansu Koparal a , Kadriye Benkli b a Anadolu University, Faculty of Sciences, Department of Biology, 26470 Eskis ¸ehir, Turkey b Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskisehir, Turkey a r t i c l e i n f o Article history: Received 10 December 2013 Received in revised form 3 March 2014 Accepted 5 March 2014 Available online 15 March 2014 Keywords: Au(III) Ru(II) Pt(II) Antitumoral activity Apoptosis Selective toxicity a b s t r a c t Around the world scientists try to design successful cures against still incurable dis- eases, especially cancers. New targets for prevention and new agents for therapy need to be identified. We synthesized novel metal complexes [Au(L1)(L2)Pt]Cl2 and [Ru(L1)2(L2)Pt]Cl2 for determining their cytotoxic and apoptotic effects. The complexes are synthesized by using 1,8-diaminonaphthalene (L1), and bis-1,4-di[([1,10]phenanthroline-5- il)aminomethyl]cyclohexane (L2) as ligands. This is the first study to examine these metals and these molecules in cancer treatment. We elucidated the effects of test compounds with embryonic rat fibroblast-like cells (F2408) and H-ras oncogene activated embryonic rat fibroblast-like cancer cells (5RP7). Results showed that our complexes are more effec- tive than cisplatin to kill ras-transformed cells. Although the [Au(L1)(L2)Pt]Cl2 compound showed a cytotoxic potency higher than [Ru(L1)2(L2)Pt]Cl2 against cancer cells, it proved to be almost five times less effective in decreasing cell viability over healthy cells. Au(III) compound selectively targets the cancer cells but not the healthy cells. © 2014 Elsevier B.V. All rights reserved. 1. Introduction It has been known for many years that metal ions such as gold(III), ruthenium(III) or platinum(II) exert a wide range of biological activities including the suppression of cell prolif- eration, anti-tumorigenic activity, prevention against HIV or malaria, and various apoptotic effects. Today, platinum-based chemotherapy is routinely employed in the clinic as cancer chemotherapy (Carcelli et al., 2013; Grazul and Budzisz, 2009). ∗ Corresponding author. Tel.: +90 222 3350580/4839; fax: +90 222 3204910. E-mail addresses: beklemb@gmail.com (R.B. Bostancıo ˘ glu), akoparal@anadolu.edu.tr (A.T. Koparal), kbenkli@anadolu.edu.tr (K. Benkli). The similarity between platinum(II) and isoelectronic gold(III) suggests that certain complexes of the latter metal centre may also have promising cytotoxicity in cancer cell (Martínez et al., 2010). Human tumours harbour multiple genetic alterations in genes controlling cell growth, differentiation and survival. These genetic changes comprise activation of oncogenes and inactivation of tumour suppressor genes. One of the most frequently activated oncogenes in human cancer is the Ras gene family. So, in humans, about 30% of the tumours carry http://dx.doi.org/10.1016/j.etap.2014.03.003 1382-6689/© 2014 Elsevier B.V. All rights reserved.