Dalton Transactions themed issue on Metal Anticancer Compounds

There is an urgent need for new drugs to treat cancer, drugs with novel mechanisms of action. What can inorganic chemistry offer?

Metal complexes appear to provide a rich platform for the design of novel anticancer drugs. We can chose the metal itself and its oxidation state, the number and types of coordinated ligands, and the coordination geometry of the complex. The ligands can not only control the reactivity of the metal, but also play critical roles in determining the nature of second-coordination-sphere interactions involved in the recognition of biological target sites, such as DNA, enzymes and protein receptors. Also, the ligands themselves can sometimes undergo biologically-important redox reactions or other modifications (e.g. hydrolysis) in vivo mediated by the metal.

These variables provide enormous potential diversity for the design of metallodrugs. They also introduce many challenges. Changes in speciation are likely to be accompanied by changes in biological activity. Hence it is important to identify the nature of the metal complex which exists in the biological medium and is undergoing the biological test, and ideally the species which reaches the target site.

Metal–ligand (coordination) bonds are usually much weaker than covalent bonds and so ligand substitution reactions will be common in biological media. Most metallodrugs are therefore ‘pro-drugs’: they can undergo ligand substitution and redox reactions before reaching the target site. A displaced ligand may itself attack a target site and controlled ligand release can play a role in the mechanism of action.

Not only do we need to understand ligand substitution equilibria (thermodynamics) under biologically-relevant conditions, but also the timescales (kinetics) on which these occur, typically nanoseconds to years. Control of kinetics can be a valuable weapon in design.

Thanks to the pioneering work of Barnett Rosenberg some 40 years ago, there is now no doubt that medicinal inorganic chemistry, and metal coordination chemistry in particular, is worthy of exploration for drug design, Thanks to Rosenberg, platinum anticancer drugs are amongst the most widely used in cancer treatment. Today the sales of platinum drugs account for around 6% of the total global market for anticancer drugs, and the newest platinum drug to be approved, Oxaliplatin, had sales approaching 2 billion dollars in 2004 alone.

It is with great sadness that we learnt of Rosenberg's passing during the final stages of the preparation of this themed issue and fitting that one of his co-inventors, Jim Hoeschele, should record our thanks to him in a memorial.

In this themed issue of Dalton Transactions are gathered original research articles and timely reviews from leading research workers in the field. Their work illustrates the critical roles which can be played by both the metal ion and its ligands, not only in reacting with the target site, but also in drug uptake, transport and target recognition.

Medicinal inorganic chemistry is in its infancy, but, as this themed issue illustrates, the exciting challenges which it presents are likely to lead to rapid progress in the next few years and hopefully to some new clinically-useful anticancer drugs.

Peter J. Sadler

University of Warwick, UK

---