Anticancer drugs for treating ovarian and colon cancer could use rare metals as weapons in the battle against these diseases. The presence of unusual metal centres in organometallic compounds presents a novel affront to tumour cells that may even beat cancer cells that have evolved resistance to conventional drugs.

Cisplatin, an organometallic compound made using the precious metal platinum to form cis-diamminedichloroplatinum(II), is perhaps one of the most familiar chemical weapons used to fight cancer. It is commonly used to treat sarcomas, small cell lung cancer, ovarian cancer, testicular cancer, and lymphomas. It was the first of a class of anticancer drugs based on platinum, which now include carboplatin and oxaliplatin. However, as with all drugs, it is not without side-effects, and some forms of cancer become resistant to platinum-based chemotherapy.

Now, researchers at the Universities of Edinburgh (Simon Parsons), Leeds (Andrew Hebden, Thakshila Amaresekera, and Patrick McGowan) and Warwick (Sabine van Rijt, Robert Deeth, Guy Clarkson, and Peter Sadler) in the UK, are looking to other rare metals, including ruthenium and osmium to help them develop novel anticancer drugs against colon and ovarian cancer, which commonly develop resistance to other drugs. Writing in the Journal of Medicinal Chemistry, the team reports a range of compounds containing these transition metals and their NMR spectra as well as details of how effective the compound are at causing significant cell death in ovarian and colon cancer cells.

The team synthesised novel half-sandwich osmium(II) and ruthenium(II) arene complexes with N-Ph-picolinamide derivatives. The N,O-binding mode was confirmed by X-ray crystallography, while their N,N-coordination was observed using proton NMR spectroscopy, which explains the dimeric structures. Metal complexes containing picolinamide ligands have previously been reported to have relevance to peptide chemistry. So, the team has looked at the influence on cancer cell cytoxicity of nitrogen, nitrogen (N,N) as opposed to nitrogen, oxygen (N,O) coordination of picolinamide derivatives containing an anchoring pyridyl ring in osmium(II) and ruthenium(II) arene complexes.

Leeds' McGowan explains that the results with ruthenium and osmium compounds are very promising as activity against ovarian cancer is high, this is a significant step forward in the field of medicinal chemistry, he says. van Rijt, lead researcher in Peter Sadler's laboratory at Warwick adds that, "Most interestingly, cancerous cells that have shown resistance to the most successful transition metal drug, Cisplatin, show a high death rate with these new compounds."

The team's earlier work demonstrated that analogues containing the heavier osmium metal ions are potently cytotoxic towards cancer cells. The current work reveals that the binding mode exhibited by picolinamide derivatives has a major part to play in this cytotoxicity. The researchers have now related this not only to their solid-state structures and to their solution properties.

"This study demonstrates that the substituents on the ligands in this type of complex can have marked effects on the configuration adopted by the complexes and their reactivity and might provide a route to 'fine-tune' and switch their biological activity," the team says.

The transition metal in these novel compounds can bind tightly to the cell's genetic material, DNA, including the DNA in rapidly dividing cancer cells and trigger apoptosis, or programmed cell death, in the cells. Of course, the DNA in healthy cells is also affected but because they are not dividing as rapidly as cancer cells the apoptosis rates are much higher in the tumour cells. The ability to fine tune the osmium and ruthenium complexes described by Sadler and colleagues might help reduce side-effects as well as staving off cancer cell resistance.

"On the basis of the examples studies here, it appears that N,N- and N,O-coordinated N-phenyl picolinamide osmium(II) and ruthenium(II) arene complexes can exhibit dramatic differences in their biological reactivity," the team concludes. "The N,N-coordinated compounds hydrolyse quickly, show selective binding to guanine [a DNA base], and exhibit cancer cell cytotoxicity, while the N,O-coordinated compounds hydrolyse slowly, display no reactivity toward guanine or adenine, and are non-cytotoxic."

Related links:

• J Med Chem, 2009, in press
• Peter Sadler

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.