Synthesis, molecular structure and evaluation of new organometallic ruthenium anticancer agents

Abstract

A number of new ruthenium compounds have been synthesised, isolated and characterised, which exhibit excellent cytotoxicity against a number of different human tumour cell lines including a defined cisplatin resistant cell line and colon cancer cell lines. Addition of hydrophobic groups to the ruthenium molecules has a positive effect on the cytotoxicity values. Evidence is provided that, after incubation of a ruthenium compound with a 46 mer oligonucleotide duplex and subsequent nuclease treatment, ruthenium is bound to a guanine residue.

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

“…Ligand L14 has previously been reported by Roshchupkina et al 18 The corresponding -diketonate ligands were prepared 19 and dissolved with stirring in toluene, followed by addition of excess aniline and hydrochloric acid. 20,21 Ligands were obtained as analytically pure compounds from solutions of hot ethanol in yields of 38-88% and characterised by 1 H NMR spectroscopy, 13 C{ 1 H} NMR spectroscopy, mass spectrometry and microanalysis. Ligands L3-6, 8 and 11 were also characterised by single crystal X-ray crystallography.…”

“…Ligand L2 (0.63 g, 2.5 mmol, 87%) 1 13 42 (m, 1H, CH), 7.25 (d, 2H, CH, 3 J( 1 H-1 H) 22 (m, 2H, CH, 3 J( 1 H-1 H) 13 L8 (0.44 g, 1.0 mmol, 67%) 1 13 Complexes 2-13 Complexes 2-13 were synthesised by addition of [pcymRuCl2]2 (1 eq), a functionalised -ketoiminate ligand (2 eq) and Et3N (2 eq). All were stirred in dichloromethane (30 mL) at room temperature overnight.…”

“…Studies showed that the more cytotoxic (N,N) complexes undergo rapid hydrolysis and bind preferentially to guanine, whereas switching the binding mode to (N,O) slows the rate of hydrolysis and switches off the activity. 12, 13 McGowan et al also Herein we report the synthesis and characterisation of a new series of (N,O) and (O,O) complexes and analysis of their biological effects, gaining an understanding of their biological mechanisms. We report on the cytotoxic potential of our library of novel complexes, with potent cancer cell cytotoxicity observed, particular against the cisplatin resistant ovarian cell line (A2780cis).…”

“…Finally, more detailed mechanistic studies have been carried out for possible damage to cellular DNA, given the ability of previous (N,N) complexes to bind guanine. 12, 13 The complexes have been assessed for double strand DNA breaks (DSB), DNA crosslinking and single strand DNA breaks (SSB) using the Comet assay to quantify levels of different types of DNA damage in single cells, in order to gain structure activity relationships.…”

“…One equivalent of either [p-cymRuCl2]2 (Scheme 2a) or [Cp*IrCl2]2 (Scheme 2b) was stirred with two equivalents of the functionalised ligand and two equivalents of triethylamine in dichloromethane. Complexes 1-18 were isolated as analytically pure complexes from methanolic solutions in yields 46-71% and have been characterised by 1 H NMR spectroscopy, 13 C{ 1 H} NMR spectroscopy, mass spectrometry and microanalysis. 14 Complexes 2, 4-14 and 17-18 were also characterised by single crystal X-ray crystallography.…”