The effect of ancillary ligand chirality and phenanthroline functional group substitution on the cytotoxicity of platinum(II)-based metallointercalators Sharon Kemp a , Nial J. Wheate a , Damian P. Buck b , Marica Nikac a , J. Grant Collins b , Janice R. Aldrich-Wright a, * a School of Biomedical and Health Sciences, University of Western Sydney, Locked Bag 1797, Penrith South DC, NSW 2560, Australia b School of Physical, Environmental and Mathematical Sciences, University College, University of New South Wales, Australia Defence Force Academy, Canberra, ACT 2600, Australia Received 20 February 2007; received in revised form 9 April 2007; accepted 10 April 2007 Available online 4 May 2007 Abstract Fifteen platinum(II)-based metallointercalators have been synthesised that utilise substituted 1,10-phenanthroline (phen) ligands, including 5-chloro-1,10-phenanthroline (5-Cl-phen), 5-methyl-1,10-phenanthroline (5-CH 3 -phen), 5-amino-1,10-phenanthroline (5- NH 2 -phen), 5-nitro-1,10-phenanthroline (5-NO 2 -phen) and dipyrido[3,2-d:2 0 ,3 0 -f]quinoxaline (dpq), and achiral ethylenediamine (en) and the chiral ancillary ligands 1S,2S-diaminocyclohexane (S,S-dach) and 1R,2R-diaminocyclohexane (R,R-dach). Their cytotoxicity in the L1210 murine leukaemia cell line was determined using growth inhibition assays. The most cytotoxic metal complexes are those that contain S,S-dach ancillary ligands and 5-CH 3 -phen intercalating ligands. One metallointercalator [Pt(5-CH 3 -phen)(S,S-dach)]Cl 2 (5MESS), displays a 5–10-fold increase in cytotoxicity compared to the clinical agent cisplatin. From DNA binding experiments there appears to be no significant difference between any of the metal complexes, indicating that neither DNA binding affinity nor the mode of binding/DNA adduct formed is the sole determinant of the cytotoxicity of this family of platinum(II)-based metallointercalators. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Anticancer; Cytotoxicity; Structure–activity; Platinum; Metallointercalator; Diaminocyclohexane; Phenanthroline; Chirality 1. Introduction The clinical agents cisplatin, carboplatin and oxaliplatin form coordinate covalent bonds with purine DNA bases, which causes a bend in the helix toward the DNA major groove and an unwinding of the helix [1]. Conversely, inter- calators are thought to derive their anticancer activity by stacking within DNA, which lengthens, stiffens and unwinds the helix [2–4]. The chemical properties of a DNA intercalator that determine why one compound is anticancer active whilst another similar compound is inac- tive are still not clearly understood and may be more than a function of their DNA binding. For instance, some interca- lators have been shown to also target topoisomerases I and II [5–9], or thioredoxin reductase (TrxR) [10]. Anticancer activity is also likely to be a function of its ability to pene- trate into cancerous cells and its transport to the nucleus. It has recently been hypothesised that some anticancer drugs, particularly platinum-based drugs may be transported to the cell by human serum albumin [11]. To better understand the structural properties of a DNA intercalator that determine anticancer activity and to develop new drugs that display lower side-effects and are able to overcome drug resistance our group has been exam- ining platinum-based metallointercalators that contain 1,10-phenanthroline (phen) and substituted-phenanthroline 0162-0134/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2007.04.009 * Corresponding author. Tel.: +61 2 4620 3218; fax: +61 2 4620 3025. E-mail address: j.aldrich-wright@uws.edu.au (J.R. Aldrich-Wright). www.elsevier.com/locate/jinorgbio Journal of Inorganic Biochemistry 101 (2007) 1049–1058 JOURNAL OF Inorganic Biochemistry