In vitro and in vivo activity and cross resistance profiles of novel ruthenium (II) organometallic arene complexes in human ovarian cancer

Abstract

Ruthenium complexes offer the potential of reduced toxicity, a novel mechanism of action, non-cross resistance and a different spectrum of activity compared to platinum containing compounds. Thirteen novel ruthenium(II) organometallic arene complexes have been evaluated for activity (in vitro and in vivo) in models of human ovarian cancer, and cross-resistance profiles established in cisplatin and multi-drug-resistant variants. A broad range of IC 50 values was obtained (0.5 to 4100 mM) in A2780 parental cells with two compounds (RM175 and HC29) equipotent to carboplatin (6 mM), and the most active compound (HC11) equipotent to cisplatin (0.6 mM). Stable bi-dentate chelating ligands (ethylenediamine), a more hydrophobic arene ligand (tetrahydroanthracene) and a single ligand exchange centre (chloride) were associated with increased activity. None of the six active ruthenium(II) compounds were cross-resistant in the A2780cis cell line, demonstrated to be 10-fold resistant to cisplatin/carboplatin by a mechanism involving, at least in part, silencing of MLH1 protein expression via methylation. Varying degrees of cross-resistance were observed in the P-170 glycoprotein overexpressing multi-drug-resistant cell line 2780 AD that could be reversed by co-treatment with verapamil. In vivo activity was established with RM175 in the A2780 xenograft together with non-cross-resistance in the A2780cis xenograft and a lack of activity in the 2780 AD xenograft. High activity coupled to non cross-resistance in cisplatin resistant models merit further development of this novel group of anticancer compounds.

Structure–activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity

“…Changing the arene from p-cymene to biphenyl and the monodentate ligand X from chloride to iodide also increases the activity significantly. Activation by hydrolysis and DNA binding appears not to be the major mechanism of action since both the highly active complex [Os(η 6 -bip)(2-F-azpy)I]PF 6 (9) and the moderately active complex [Os(η 6 -bip)(3-Cl-azpy)I]PF 6 (23) are very stable and inert towards aquation. Studies of octanol/water partition coefficients (log P) and subcellular distributions of osmium in A2780 human ovarian cancer cells suggested that cell uptake and targeting to cellular organelles play important roles in determining activity.…”

“…2,3 For example, Jaouen et al have designed ferricenium complexes which target hormone receptors in breast cancer cells, 4 certain Ru II arene complexes are active in vitro and in vivo, [5][6][7] , 8 and a few reports of anticancer active organometallic osmium complexes have recently appeared. [9][10][11][12][13][14][15] Osmium complexes are often considered to be relatively inert (a common characteristic of low-spin d 6 metal ions and especially 3 rd row transition metals). 16,17 Organometallic Os II and Ru II arene complexes can adopt very similar threedimensional structures.…”

Iron(III) Pincer Complexes as a Strategy for Anticancer Studies

“…Among them, a series of arene-ruthenium complexes such as RM175, RAPTA-C, RAED-C, and UNICAM-1 have shown very promising therapeutic effects. [8][9][10][11][12] Additionally, a class of cyclometalated ruthenium complexes known as RDCs (ruthenium-derived compounds) has shown particularly good activity as anticancer agents, for both in vitro and in vivo studies. [8,13] Various reports have shown that the mechanisms by which phenylpyridine derivatives exert their anticancer effects are presumably not through DNA interaction, as in the case of cisplatin, but in part through redox reactions with oxidoreductases.…”

Hypoxia-Sensitive Metal β-Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis

“…Most importantly ruthenium is thought to have slow in vivo ligand exchange and higher selectively towards cancer cells leading to lower toxicity. [1][2][3][4] The discovery of organometallic ruthenium complexes first began with the library of [( 6 -arene)Ru(II)(en)X] + (X = halide, en = ethylenediamine) complexes synthesised by Sheldrick et al [5][6][7] The effect of the ligand was later explored by Sadler et al substituting the neutral (N,N) ethylenediamine ligand for an anionic (O,O) -diketonato ligand, showing a significant increase in cytoxicity of the complexes. 8 In collaboration with Sadler, McGowan et al first synthesised picolinamide Ru(II) and Os(II) arene complexes due to their relevence to previously reported metal ion-peptide chemistry [9][10][11] and the possibility of different binding modes, through either a monoanionic (N,N) or a neutral (N,O) form.…”