Oxidative processes - from amino acids to heterocycles, complexity from simplicity

In our search for better medicines to improve healthcare in an ageing population, for safer agrochemicals to aid food production for a growing population, and for improved materials for reprographics and electronics to match our insatiable desire for new technology, chemical synthesis will play a dominant role. Without synthesis the new molecules required to address such issues will simply not be available.

In searching for efficiency in synthesis, we can learn much from Nature, whose biochemical machinery can convert simple building blocks into complex molecules. Hence the overall aim of this Proposal is to emulate the ingenuity and efficiency of Nature in the arena of oxidation, a topic that is fundamental not only to chemical synthesis, but to life processes in general. We will develop new strategies using oxidative processes for the construction of complex biologically active molecules that comprise nitrogen-containing (heterocyclic) rings from simple amines or amino acids - complexity from simplicity.

Oxidative processes in Nature depend upon oxygen, and therefore we propose to develop new oxidative protocols that use a catalytic amount of a non-metal oxidant, compounds known as quinones, in the presence of air/oxygen as oxidant. This protocol will then be employed in the oxidation of a simple tryptophan tetrapeptide to form more complex molecules that will then serve as precursor to the structurally unique anticancer compound diazonamide A. Two further oxidative processes are then planned to finalise the complete diazonamide framework, an overall increase in complexity from five rings to ten in just three oxidative steps.

We will further demonstrate the power of oxidative processes in the synthesis of the unusual heterocycle violatinctamine, a fascinating molecule very closely related to the natural pigments of human red hair. Again, we approach the problem using oxidative transformations of simple building blocks - amines and aminoacids such as dopamine, cysteine and phenethylamines - to form a more complex, and biologically relevant molecule.

Natural compounds from the oceans often possess potent medicinal activity, and there are already three marine derived drugs in clinical use. However, full biological evaluation of such natural substances is usually hampered by lack of material, and chemical synthesis is the only recourse to obtain enough material for study. The pterocellins are a case in point. They possess anticancer, antibacterial and antifungal activity, and although they have been obtained by chemical synthesis, a more efficient route is required. We speculate that well known naturally occurring substances known as beta-carbolines serve as precursors to the pterocellins via a series of oxidative processes, and propose to demonstrate this in the laboratory. Thus simple beta-carbolines, readily available from tryptamines, can undergo oxidative transformation into the complex oxygenated structures exemplified by the medicinally active heterocyclic compound pterocellin A.

The Proposed Research derives inspiration from natural routes to complex molecules that possess biological activity. Oxidative processes are at the heart of all the proposed work, and feature throughout as pivotal steps, often initiating a cascade of reactions that result in extremely efficient syntheses, embodying the principle of complexity from simplicity. The methodology is illustrated in routes to a range of heterocyclic molecules, a class of compounds of enormous commercial importance. The strategies and chemistry embodied in the Proposal will enable the facile preparation of a wide range of heterocyclic ring systems, and will impact on the UK fine chemicals industry. All concerned with the development of new medicines, agrochemicals, reprographic materials etc, where heterocyclic compounds completely dominate the field, will benefit immediately from the proposed research programme.

The proposed research is in two areas - heterocyclic chemistry and oxidative processes - both of which have the potential for significant impact.

Heterocyclic compounds, cyclic molecules in which at least one C atom is replaced by a heteroatom (commonly N, O or S) account for well over half of all known organic compounds. Many classes of natural products, as well as a majority of commercially important medicines, agrochemicals, dyes etc contain heterocyclic rings. Hence the synthesis and study of such compounds, in particular N-containing rings, is a subject of immense importance both for academia and industry. The commercial impact of heterocyclic compounds is amply demonstrated by the list of best selling pharmaceuticals - in last 12 months, over half of the top 20 best sellers were N-heterocycles with combined sales of over $60 billion. Therefore the proposed Project will impact on all those in the fine chemicals industry in the UK, the EU and globally who use heterocyclic chemistry in the development of new medicines, agrochemicals, reprographic materials etc.

The proposed new strategies involving oxidative processes to streamline synthetic routes will impact on all those working in the chemical industry, where the design of safe, efficient, clean and green routes to key materials is of paramount importance. The specific proposal to develop catalytic variants of oxidations using quinones such as DDQ will also have far reaching impact. DDQ is an excellent organic oxidant that is very effective for a number of transformations. However, it does have problems - it is quite expensive and toxic, and generates large amounts of a byproduct - and therefore its use has been limited. The catalytic use of DDQ with air/oxygen as the terminal oxidant obviates all these problems and would have major impact in terms of safety, cost, the environment and, of course, efficiency in synthesis.

The compounds to be studied in this Project were selected not only because of their proposed accessibility by oxidative processes, but also because of their reported biological activity, particularly as potential anticancer agents. If compounds arising from this Project have suitable medicinal properties, then there is huge potential impact on enhancing healthcare, although the timescale for drug development is long. Nevertheless, the proposed collaborations will have immediate impact on biological scientists - the Project will contribute a wide range of novel chemical entities for biological evaluation and potential exploitation as therapeutic agents. If significant biological activity is observed, we will consider the impact on intellectual property and the commercial implications, facilitated by the University's Research and Innovation Services and by the School of Chemistry's own Business Development Manager.

At the personal level, the Project will have a very major impact on the postdoctoral researcher himself/herself. Not only will it enhance their research experience and scientific knowledge, it will also provide a chance to participate in a range of training opportunities. Not only will they attend regular research seminars, they will also benefit from a wide range of University training courses dedicated to the career development of postdoctoral colleagues. Hence the Project will produce a highly trained and experienced postdoctoral researcher (together with associated MSci project students) who will be well equipped to impact on UK science in future years.

Finally, if potential new therapeutic agents do arise from this Project, there is an excellent opportunity for impact on the public awareness of science. The general public find it easier to relate to the discovery of a potential new drug than to the discovery of a new gene or cellular pathway, and the fact that the new drug might be based on something from Nature adds greatly to the impact.