The Linchpin Strategy in the Array Synthesis of Diverse Bioactive Ligand Scaffolds

The discovery of new drugs to treat diseases afflicting modern society is a huge challenge for chemists. For every drug that enters clinical usage, it is necessary to make and test around 10,000 candidate compounds, and total costs for the discovery programme can approach 500 million. The pressure to deliver new drugs in a cheaper, faster and more efficient manner means that chemists have to be able to deliver large numbers of drug candidates in an efficient manner. One of the techniques used to do this is so-called array chemistry, where compounds are prepared in a matrix form: for example, eight compounds of type A are simultaneously reacted with eight compounds of type B to deliver sixty four new compounds. Such an approach lends itself to automation and much of this chemistry can now be delivered efficiently and automatically by robotic synthesisers. However, there is a drawback to this array approach as it stands. Imagine the interaction of the drug molecule with its target receptor or enzyme as being like a key (the drug) fitting in a lock (the receptor/enzyme). At the start of the drug discovery process, we have the lock but no key. The chemist, like a locksmith, would take a backbone (a blank key) and decorate the backbone with different substituents (corresponding to the different arrangements of teeth on the key which code for the lock). We can therefore see that both the backbone AND the pattern are important - it is no good making hundreds or thousands of Yale keys if the lock is a Chubb design. However, until now most chemical methods for the array synthesis of large numbers of compounds as potential keys only allow chemists to work on one type of backbone at a time. It would clearly be more efficient to have a method that allows us to simultaneously vary the type of keys we make whilst still retaining the ability to alter the patterns of the teeth on the key, which will allow them to selectively interact with the desired lock . How can we achieve this?The work undertaken here will develop a new method for the synthesis of arrays, based on the use of linchpins . These are small molecules which will allow us to join together two, three or four different commercially available components in a controlled manner. Once the components are linked together, we can change the shape of the backbone by getting the individual components to react together to form ring-shaped molecules. For example, if we joined three components A, B and C together on the linchpin, we could leave the backbone alone, or we could cyclise it by joining A to B, A to C, or B to C. Each of these four possible options will have a very different shape, and hence gives us different backbones to our keys for drug discovery, as well as still being able to vary the nature of A, B and C (ie the teeth of the key). The challenge in all of this is developing methods for addition of the various components to the linchpin which are mild enough not to destroy the groups that we will use to join the components together in the cyclisation, and this is what will be studied in the current grant.