Research objectives and content
The purpose of the proposed research is to develop a focused program in the area of bioreductive anticancer agents by the design and synthesis of novel indolequinone based pro-drugs. A key aim is to exploit the combination of hypoxia and the presence of reductases in tumours to deliver specif1c agents (e.g enzyme inhibitors) which target processes important for tumour growth. The essence of the proposal, the molecular basis of which has already been demonstrated in key preliminary experiments. is to |design a reductively activated indolequinone, which can specifically deliver, selectively, inhibitors of processes important in tumour development. Thus it is proposed to prepare and fully evaluate a number of novel indolequinones, incorporating agents to target specific enzymes and growth factor receptors. The indolequinones that have been designed to study incorporate potent inhibitors of tyrosine kinases, nitric oxide synthase and tubulin assembly, that are linked to the bioreductively activated pro-drug by a metabolically stable covalent bond, thereby ensuring that the drug is released only under bioreductive conditions in hypoxic regions of tumours.
Training content (objective, benefit and expected impact)
The proposed project will provide a thorough grounding in the chemistry of heterocyclic compounds based on the indole ring system. Indole rings occur widely in Nature and are often incorporated into a range of biologically active compounds, and hence their study is a subject of immense importance. The host laboratory is one of the world's leaders in indole chemistry, and will be able to provide a wealth of expertise from which the applicant can benefit. The proposed research on novel antitumour compounds will make a major impact in the chemotherapy of cancer, since it relies on mechanisms which are specific to tumour cells.
Links With industry / industrial relevance (22)
The synthesis of new chemotherapeutic agents is a subject of immense importance given the biological activity of, and commercial interest in, such compounds. The host laboratory has established links with industries, notably in the pharmaceutical sector, with relevant interests. In particular, GlaxoWellcome, with research centres both in the UK and Italy, have taken an active interest in our work, and links have been established for future applications of our research.