Natural products display a high diversity of distinctive molecular architectures, and often exhibit unique biological properties. An important objective for discovering compounds with new biological activities is to develop straightforward methods to synthesise new molecular scaffolds with defined three dimensional shapes. Our group explores the scope of using metal complexes to accomplish this goal, Meggers told OBC. 

1. Could you briefly explain the focus of your article?

The article describes a general and economical synthetic route to a class of ruthenium half-sandwich protein kinase inhibitors which mimic the overall shape of the indolocarbazole alkaloid family. More than a dozen derivatives were synthesized and some functionalizations were found to have a profound effect on the property of this scaffold. For example, the incorporation of a fluorine into the pyridine moiety increases the binding affinity for glycogen synthase kinase 3 (GSK-3) by almost one order of magnitude. A protein co-crystal structure demonstrates that this low nanomolar organometallic inhibitor binds in the ATP-site of protein kinases like a typical purely organic inhibitor.

2. What is your particular interest in this area of research?

We explore the ability of substitutionally inert metal centers to help define and build unique shapes of small molecules. We hope that such an access to unexplored chemical space may lead to the discovery of molecules with unprecedented properties.

3. Where do you see this field developing in the future?

Currently, chemical biology and medicinal chemistry are predominately focused on organic molecules. We envision that in the future substitutionally inert organometallic compounds will become common scaffolds for the design of molecular probes and even drugs. In contrast to metal drugs such as cisplatin, in these compounds the metal is supposed to play mainly a structural role.

4. Are there any particular challenges facing future research in this area?

It has to be demonstrated that such metal complexes can be nontoxic in vivo and we have to determine the fate of the metal. Can we develop a safe and nontoxic drug that is based on a kinetically inert ruthenium complex?