Total syntheses of vioprolides for further biological evaluation

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Human cells have various processes to protect themselves from bacterial and viral infections. Some of these processes are mediated by signalling pathways that alert the cell to a threat and initiate a response. Interferon mediated pathways are essential for cell defence. The NF-kB pathway is linked to inflammation and specifically to chronic inflammatory bowel disease in humans. These pathways can be influenced by a range of "small" molecules and the study of how such compounds can activate or moderate these pathways is of considerable interest in the context of understanding them more thoroughly and with the development of new therapies for a range of viral and inflammatory diseases. The vioprolides are a group of modified cyclic peptides isolated from a myxobacterium that have been shown to have a synergystic activating effect on an interferon mediated pathway in cells and a moderating effect on the NF-kB pathway. Unfortunately the quantities of vioprolides that are available from the natural source are very limited indeed and are restricting further studies into the biological effects of these compounds. It is proposed to develop syntheses of these vioprolides from simpler commercially available compounds so that the biological studies can be resumed. Moreover once these syntheses are complete, it should be possible to modify them to provide analogues of the naturally occurring compounds in order to study aspects of the effects of structural changes on the biological activities of these compounds. These syntheses will be challenging in themselves although by using a convergent approach it is hoped that the longest linear route will be no more than 20 steps long. The syntheses will not be straight forward since embedded within the structures of the vioprolides are features that made them very sensitive to certain chemical reagents. However, based on preliminary studies an approach to these compounds has been put forward and will be the basis of the work to be carried out with the support of this grant. Finally, it should be noted that the vioprolides are active at the nanogramme level. So the synthesis of tens of milligramme quantities should provide enough material for biological studies to continue although it it hoped to prepare at least one vioprolide on a hundred milligramme scale.