Synthesis of complex aminoacids and the microsclerodermins

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry


The development of new reactions is one of the most pressing goals for modern synthetic organic chemistry because chemical industry has an ever increasing requirement for selective, efficient and environmentally friendly chemical processes. We aim to develop methods that will allow the rapid and efficient synthesis of complex aminoacid containing natural products with intriguing biological activity. Over recent years we have built up a knowledge of methods for oxidising alkenes and in so doing providing building blocks that are the perfect materials from which to accomplish the synthesis of aminoacids. The goal of this proposal is to convince the reader that (i) the synthesis of the natural product microsclerodermin (which is a potent anti-tumor agent) is a worthwhile and high impact area of research; (ii) that the synthesis itself will drive the development of new methods and reagents that are useful in many other applications, especially in the construction of complex aminoacids and peptides; (iii) we have the experience and expertise with these types of compound to ensure success and completion of the synthesis. As appropriate to such a complex undertaking, we have access to a wide variety of biological screens, especially those that search for anti-cancer activity, and tests will be performed on the final compound and intermediates formed en-route. This should ensure the biggest return of new scientific information for a relatively modest outlay. The chemistry described in this proposal is interesting and useful because it will enable us to prepare a complex natural product that has never been prepared before in a short and efficient sequence. We will be forced to explore the limitations of several organic methodologies as we go, and this will lead to more powerful methods for alkene oxidation and for the preparation of peptides via a fundamentally new route. In addition to the sheer chemical challenge posed by this molecule, it is surely a worthwhile task to screen it, and precursors to it, for the exciting biological activity that has been reported. The chemistry described herein is high impact and contains an ideal mix of methodology and synthesis; it has significant back-up plans (such as the stand-alone synthesis of peptides and aminoaclohols) and publication milestones, and will uncover really interesting and useful reactions as well providing an excellent training for a PDRA. We also have the experience with synthesis and with these types of molecules to ensure that the project is finished.

Planned Impact

The beneficiaries of this research outside of academia include: chemical industry including the pharmaceutical industry; the agrochemical industry; the fine chemical industry. These beneficiaries will be able to exploit the chemistry described in this proposal to achieve the synthesis of aminoacids and peptide derivatives in a more efficient way. These compounds are extremely important molecules with many uses (for example, several commercial drugs contain an aminoacid or a peptide chain) and, therefore, this regime will allow industry to make commercially valuable compounds in a new way, giving them a competitive advantage. Each of the beneficiaries above improves the quality of life and the wealth of the nation, through the application of novel organic chemistry. Chemical industry plays a big role in the U.K. economy (1999 UK trade surplus in medicines was 2060 million) and the U.K. has a strong pharmaceutical industry, who stand to benefit from this methodology. Clearly, it is important that I engage with potential end-users of this chemistry so that I can ensure the project makes a maximum impact in the most relevant areas of research. I have several plans for publicising the work and for getting industry feedback on our routes as they develop. The easiest way to publicise our work is to deliver lectures in industrial laboratories, followed by a discussion of the potential applications (I have given 9 such lectures at pharmaceutical companies since 2007, and I already have 3 more invitations for 2010). Since appointment in 1994, I have had many CASE type collaborations with industry and sent nearly 30 people to full-time employment in various industrial chemistry laboratories; so I have many relevant contacts within the industrial organic chemistry community. I have been, will continue to be, very active in publicising our methodology and gaining feedback on useful applications of it. The timescale involved in giving a benefit to the end-users of the research is short (months rather than years): as soon as new routes are developed and publicised then they can be used in industrial laboratories. Clearly, routes to established drug candidates are not changed lightly, and it may take longer to make an impact on a drug development scale compared to a medicinal chemistry setting. However, the improvements in efficiency and scalability will be worth it. Full details of our plans for exploitation and collaboration are given in the Impact Plan.
Description New ways to make biologically active compounds, especially complex bioactive peptides. The synthesis of a complex and biologically active compound was prepared and its structure was revised because of the synthetic efforts.
Exploitation Route Used in chemical synthesis, especially of unstable and active compounds. New routes to anti-fungal agents have now become viable.
Sectors Pharmaceuticals and Medical Biotechnology