"Cancer is a common and life-threatening disease with world-wide occurrence, and the number of affected individuals and morbidity continues to increase annually. It is therefore of great importance that straightforward syntheses of potential anti-cancer agents are developed in order to advance treatment and drug discovery in this field. The disorazoles, the subject of this proposal, are a group of natural products which display strong anticancer activity against a variety of cell lines, including multidrug resistant cells. Although one total synthesis and several approaches have been published towards the key family member disorazole C1, these are lengthy and poor-yielding. Consequently, a more-detailed investigation of the mode of action of this highly potent tubulin inhibitor has been severely hampered. The synthetic approach outlined in this proposal will dramatically increase the convergency of synthesis and will allow us to explore how changes in one of the key structural features affects the natural product structure and function. Working in the Hulme group laboratories, the Fellow will synthesise the disorazole C1 analogues with a pioneering approach to construction of the macrolactone core. Using computational modelling and a range of traditional and cutting-edge technologies (X-Ray, NMR and IM-MS) he will study the analogues' structures and tubulin-binding abilities. The Fellow will conduct biological tests including cell-based assays in-house, exploiting the world-leading expertise and facilities within EaStCHEM. The project is thus ideally placed to offer the Fellow a broad interdisciplinary training and give him new insights into both traditional and modern chemical biology and medicinal chemistry techniques. He will attend a series of training courses, tutor and lecture to undergraduates, and exercise considerable supervisory responsibility within the research group; thus enhancing his long-term prospects of becoming an independent academic researcher."
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