Diels-Alder/Ene Reactions for the Multi-Component Synthesis of Natural Product Inspired Bioactive Chemical Libraries

Despite the many fantastic advances in health treatment over the past 50 years new drug molecules are always needed. Sometimes this is to combat existing health problems for which a solution is yet to be found, such as some cancers, and sometimes this is to deal with emerging problems, such as the rise of drug resistant bacteria (e.g. MRSA). Modern drug discovery relies on chemists to make new molecules for testing as potential drugs which can be then optimised to for use by a patient. However current approaches to this problem can be very time consuming and inefficient. The inefficiency of these processes also results in the creation of large quantities of chemical waste which can in turn cause environmental problems. This project aims to find a solution to this through the use of one-pot chemical reactions where, in place of sequential chemical transformations (one after the other), several can happen in the same reaction flask. This efficient approach leads to a vast reduction in the waste generated, whilst at the same time increases the number of different molecules a chemist can make in a day and thus the number of molecules which can be tested. Making many molecules, rapidly and with a reduction in waste can only help to speed up the drug discovery process.Specifically this project will develop new one-pot methods to make a library of very different molecules, very quickly. The molecules we will target have the potential to be new anticancer or new antibacterial agents, so will also test these molecules as lead compounds for treatment of these diseases.

The development a new approach for the efficient synthesis of complex drug-like molecules will benefit pharmaceutical, agrochemical and speciality synthesis companies, areas in which the UK has historical strengths. On completion and publication of the work (1-2 years), the flexibility and wide scope of our methodology will allow direct application to the synthesis of both focused and diverse libraries based on target molecules of commercial interest. Improvements in efficiency and greenness in the generation of drug-like libraries combined with the associated time savings will provide direct benefits to companies utilising this approach. Both our planned compound libraries and any commercially generated libraries have the potential to be important leads in the development of new drugs for the treatment of cancer and other diseases. Drug development is a long process; however the potential exists for this work to result in the generation of new treatments of cancer or bacterial infections within 10-12 years. With a continued need for anticancer treatments and the rise in drug resistant bacteria, our contributions to this field will provide important progress towards the development of new drugs, through increased understanding of the requirements of successful molecules for these targets. The ultimate production of a new drug will provide direct benefit to the health of the general public as well as providing considerable revenue for those organisations controlling the intellectual property. The progress towards any new disease treatment within the UK will also grab the attention of both the UK and worldwide public. This will result in both continued public and government support for scientific research and will serve to inspire new students and researchers to pursue careers in scientific research. Through direct contact with both Cancer Research UK groups and the antibacterial specialist company Demuris, positive results from our work will have direct measurable effects on the competiveness of our collaborating groups (a medical charity and a commercial drug development company respectively). The project team (PI and DTA student) will also gain invaluable experience in working with members of medicinal chemistry and biology groups leading to further work and subsequent future developments in the area.