Synthesis of novel arginine analogues as potential therapeutic agents to combat mesothelioma

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In developing a new therapeutic agent, there are two questions to address: i) how to get the drug to the specific site in the body where it is needed and ii) does it do what we want it to do at the target site and without undesirable side effects. These requirements are incredibly challenging e.g. how do you ensure that an anti-cancer drug reaches the tumour and only kills tumour cells and not healthy ones? This project addresses these key issues within mesothelioma.Human malignant pleural mesothelioma (MPM) is an aggressive (fatal) lung cancer which is always associated with asbestos exposure. Typically symptoms do not appear until 20-40 years after the original exposure, with life expectancy then 12-18 months. Given the widespread use of asbestos during the 20th century and this long latency period, it is no surprise that cases of MPM continue to rise. Therefore there is an urgent need to develop novel therapeutic approaches for the treatemnt of MPM.The amino acid arginine is essential in the development of various lung cancers. While most healthy cells are able to produce their own arginine, the majority of MPM tumours have lost the function of the gene ASS1, which is specifically responsible for the production of arginine. Thus MPM cells have lost the ability to produce arginine themselves and instead have to obtain it from the blood. It has already been shown that depriving MPM tumours of arginine slows their growth and eventually kills them: the 'achilles heel' of lung cancers.The overall aim of the project is to address the problems of drug delivery and site selectivity within MPM by developing a series of bifunctional molecules, designed to solve both problems simultaneously. The underlying principle is simple: rather than depriving a tumour of arginine, we will use the arginine structural motif as a targeting system to deliver a highly potent anti-cancer agent directly to the tumour. The project will involve the synthesis of a library of derivatives of arginine attached to a linker unit and then a toxic moeity, all specifically designed such that the arginine-portion of the bifunctional molecules will be rapidly absorbed by the arginine-dependant tumours, simultaneously delivering one (or more) attached anti-cancer agents directly to the heart of the tumour. The project will also involve the biological evaluation of all the compounds prepared.