Birmingham chemists lead on safer, more effective pharmaceuticals

The demand for new drugs to treat a range of medical conditions has never been greater. As well as a need for safer and more effective treatments for familiar diseases and illnesses, ranging from arthritis to cancer, we face new threats from drug-resistant ‘super bugs’ and viral diseases like Ebola.

The pharmaceutical industry has struggled to meet these challenges, and in many cases the new medicine pipelines have run dry. One of the many reasons for this, says Professor Nigel Simpkins, is that industry has not always used the right kinds of compounds as candidates for medicines, which has led to late-stage attrition in clinical trials.

The pharmaceutical industry is now moving to address these issues by engaging with the academic world in order to identify new biological targets and also to employ high quality molecular scaffolds in the drug discovery pathway.

Professor Simpkins, the University’s Haworth Chair of Chemistry, is actively engaged in this area of research in collaboration with the global biopharmaceutical company AstraZeneca (AZ). As an organic synthesis chemist, he works on inventing new methods for the synthesis of significant target molecules, including drug-like substances and natural products.

Nigel’s current research focuses on the chiral – or handed – approach to the synthesis of molecules that are formed by linking together two amino acids, with the help of naturally occurring catalysts. In particular, catalysts derived from the cinchona alkaloid quinine, a famous anti-malarial drug and constituent of tonic water, are extremely good at producing molecules in their single chiral form.

A molecule is chiral if there exists another molecule of identical composition, but which is arranged in a non-superimposable mirror image form. Human hands are perhaps the most universally recognised example of chiral objects; hence the term ‘handed’ in relation to molecules.

‘Chiral molecules can be right- or left-handed; you can have a left hand molecule that smells of lemon and a right handed one that smells of orange,’ explains Nigel.

The body is a ‘handed entity’: all of our proteins and carbohydrates are of a single chirality, so the way the body interacts with molecules needs to be like a handshake. In order to get it right – rather than cause an unwanted effect – we need efficient methods for synthesising molecules as a single chiral form (called an enantiomer).

So exploring efficient new methods for chiral – or enantioselective – synthesis of new molecules that could end up in the body as medicines is an important area of research.

Nigel recently had a paper published in the Royal Society of Chemistry journal Chemical Science, entitled ‘Highly enantioselective access to diketopiperazines via cinchona alkaloid catalysed Michael additions’.

The paper, co-authored with Alejandro Cabanillas, Christopher D Davies and Louise Male, is the result of a collaborative PhD studentship with AZ, which is continuing the collaboration with both a new studentship and a postdoctoral researcher who will work at the AZ site near Manchester.

‘This new chemistry enables us to make many kinds of unnatural amino acids, and also diketopiperazines (DKPs), which are a class of organic molecules in which the two amino acids are linked together in a six-membered ring,’ says Nigel. ‘These occur in Nature and in the human body, eliciting different physiological responses.

‘Amino acids are a biologically important family of organic compounds, and diketopiperazines are known to have drug-like properties. If you’re trying to make new medicines, it’s now recognised as very important to be able to access libraries of these sorts of compounds. Our new chemistry provides highly efficient access to these types of molecules. The crucial thing is that it gives you completely one hand and not the other, which we call selectivity.’

Nigel continues: ‘This is our first paper in this area of research, so there’s still a long way to go in developing the new chemistry and applying it to make the kinds of molecules that the industry needs. We are a long way from delivering a new drug molecule, but the chemistry has the potential to provide important chiral scaffolds: one of these compounds could become a new medicine.’

 

Notes

The paper by  Alejandro Cabanillas, Christopher Davies, Louise Male and Nigel Simpkins titled "Highly enantioselective access to diketopiperazines via cinchona alkaloid catalysed Michael additions"  was published by the Royal Society of Chemistry.

The paper also received College of Engineering and Physical Sciences Best Publication Award for February 2015.