Novel strategies to access chiral heterocycles as potential lead compounds in drug discovery

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The development of new medicines (drug discovery) is essential to improve the health of the world's population. Tackling current medical needs requires drugs that will work in new ways. Therefore, more complex biological interactions are being investigated as targets. However, finding good starting points for drug development that will act against these complex biological targets presents a formidable challenge.Historically, starting points for drug development, known as lead compounds, came from natural small molecules that bind to the target. However, these are often not available, particularly in complex binding interactions. The screening of compound collections in the pharmaceutical industry has also been largely unsuccessful in finding lead compounds for more complex targets. This is because industrial compound collections are often clustered around relatively few structural types and are frequently reliant on flat (non-chiral) structures. Alternative methods are required for the generation of more diverse and 3-dimensional (chiral) molecules that may function as drug-leads. Indeed the pharmaceutical industry is currently interested in focussing on fewer, higher quality lead compounds.This research will develop new chemical methods to enable the synthesis of diverse molecular frameworks with the potential to be lead compounds in drug discovery. These frameworks will be centred around chiral (3-D) heterocycles. Heterocycles are carbon based ring structures that contain at least one heteroatom in the ring (i.e. an oxygen, nitrogen or sulphur atom) and are frequently essential components of drug compounds. Chiral heterocycles in particular offer ideal properties for quality lead compounds, being small with desirable physical properties as well as having a defined 3- dimensional shape, which is crucial to structural and binding interactions with biological systems.The synthesis of these complex heterocyclic molecules from simple, readily available starting materials is of fundamental interest and a major synthetic challenge. The key synthetic innovation of this proposal is the invention, development and application of new chemical reagents to achieve this goal. These reagents contain multiple functionality, important in performing multiple roles in the synthesis. Synthetic methods will be developed for three classes of chiral heterocycles with control of the 3-D shape. Furthermore these synthetic methods will allow a wide variety of chemical groups to be introduced directly onto the heterocyclic core of the molecule. This will enable rapid access to diverse molecular frameworks not currently well represented in industrial compound collections.Compounds generated by these new methods are of interest as potential lead compounds against a wide variety of biological targets. To demonstrate this, a series of analogues will be prepared of a compound known to disrupt the interaction between two proteins that is implicated in various types of cancer. Future collaborative research is envisaged to evaluate the now accessible compounds against biological targets. Furthermore, the new chemical reagents and the synthetic methods developed in this research will be widely applicable in fields of chemical synthesis and medicinal chemistry.