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Towards an enantioselective synthesis of Plakortide P and its application to the development of drugs for the treatment of Chagas disease

Final Report Summary - PLAKORTIDE (Towards an enantioselective synthesis of Plakortide P and its application to the development of drugs for the treatment of Chagas disease)

Chagas disease, African sleeping sickness and leishmaniasis are all examples of orphan diseases, so named because of the overall lack of attention given to them by major pharmaceutical companies. This is often in spite of the fact that many millions of people may be affected by these diseases worldwide. The infectious agent of Chagas disease is Trypanosoma cruzi, which is closely related to the parasites which cause African sleeping sickness and leishmaniasis. The parasite usually enters the bloodstream of mammals through blood-sucking insects e.g. assassin bugs. Between 8 to 11 million people in Mexico, Central America, and South America are estimated to have Chagas disease, most of whom do not know they are infected. If untreated, infection is lifelong and can be life threatening. The acute phase of the disease is characterised by symptoms such as fever, fatigue, body aches, headache, rash, loss of appetite, diarrhoea, and vomiting. In the chronic phase, the disease may result in cardiac complications, such as heart failure, or intestinal complications. The average life-time risk of developing one or more of these complications is about 30% with a fatality rate of around 50,000 people per annum. The overall goal of this project is to develop new synthetic routes to chiral cycloperoxides, compounds which are known to be active against T. cruzi, the causative agent in Chagas disease.

The specific aim of this project is to answer the following questions: 1) Can the enantioselective peroxidation of unsaturated ketones be developed and applied to a synthesis of chiral cycloperoxides? 2) Can this methodology be applied to other cycloperoxides including those with anti-malarial activity? 3) Can high potency analogues be synthesised through modification of the major side chain of these cycloperoxides and will stabilisation of radical metabolites lead to novel analogues with improved activity? 4) Can such analogues provide insights into the structure activity relationship of these cycloperoxides?

Over the course of this project, we have made a number of significant finding, key amongst which are:
i. The development of a new methodology for determining the enantiomeric excess of beta-peroxyacids by derivitisation with methyl D-mandelate.
ii. Optimisation of the cinchona-based catalyst system for the asymmetric peroxidation of unsaturated aldehydes, with an increase of enantioselectivity from 33% to 72%.
iii. Development of a wholly novel prolinol ether-based catalyst system for the asymmetric peroxidation of unsaturated aldehydes, with ees in excess of 90%.
iv. Development of a novel silver-mediated cyclisation of butylperoxides to afford chiral 5-membered cycloperoxides.
v. Development of a related approach for the preparation of chiral 6-membered cycloperoxides
vi. Development of synthetic route for the incorporation and modification of different sidechains to the cycloperoxide core, including those based on Plakinic acid, a compound with known antiparasitic effects.

Having overcome a number of challenging obstacles in the synthesis of these compounds, we have now developed a robust methodology for the preparation and modification of chiral cycloperoxides. We expect to have a number of compounds available for biological testing by our partners in the University of East Anglia within the next 12 months.

This project has been very beneficial to our research group, allowing us to bring a highly experienced Indian postdoctoral fellow to expand into the exciting area of organocatalysis and its application to the development of new drugs for neglected diseases. In addition to the skills and knowledge brought by the fellow to our group, he has also acted as a mentor to other students over the period of the fellowship and this has been an invaluable experience for them. The work has been highly productive scientifically, with a recent publication in the peer-reviewed journal ‘RSC Advances’ as well conference publications at the North West Organic Chemistry Symposium Liverpool in 2012 and the 65th Irish Universities Chemistry Research Colloquium Dublin, Ireland 2013. The contribution of the fellow has acknowledged at the “Ireland Champions of EU Research” event in June 2012. Furthermore, on foot of this research, we have been able to draw down additional funding for a four year PhD scholarship from the Irish Research Council to continue this project.

The transfer of knowledge aspect of this IIF fellowship has not only been from India to the EU, but also in the opposite direction. The IIF fellow has completed a number of training modules over the course of his fellowship, many of which have an emphasis on transferable skills in the areas of both research and teaching. These are lifelong skills which he can take back to India. We also intend to develop an Ireland-India collaboration involving the future transfer of students between India and Ireland, as well as sharing our research infrastructure in Ireland with India. Indeed, we have already recruited an Indian PhD student through the fellow's network of contacts to continue on this work.

The challenging, interesting and rewarding basic science which this IIF fellowship has enabled us to carry out over this 24 months period lays the groundwork for the future development of compounds which could have a highly beneficial impact on many millions of lives. We are determined to bring this work to a successful conclusion and are confident that we will achieve this outcome in the not too distant future.