Total syntheses of vioprolides for further biological evaluation

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.

The vioprolides are complex compounds that have yet to be synthesized. The synthetic work will therefore be extremely challenging and will be publishable in international journals of chemistry, so contributing to the reputation of UK organic chemistry. The PI will also present the work at international conferences of organic chemistry.

Th work will also test synthetic methodologies that provide access to cyclic depsipeptides and cognate structures to the limit and will deliver an excellent training for the post-doctoral researchers involved.

Improved understanding and control of cellular responses to viral and bacterial infections will aid the development of new medical therapies. The interferon pathway is an important process by which cells respond to infection. Indeed recombinant human alpha-interferons are used for the treatment of several diseases whilst a beta-interferon is certified for the treatment of multiple sclerosis. An understanding of the mechanistic basis of the synergistic effect of vioprolides on the murine type 1 interferon signalling pathway will lead to better appreciation of crucial IFN signalling processes. This improved understanding of the IFN pathways will contribute to the development of improved therapies for viral diseases and cancer. The NF-kB pathway is linked to chronic inflammatory bowel disease in humans. The systems biology of the NF-kB pathway is being studied to improve the understanding of inflammatory bowel disease. It has been shown that vioprolide A modulates the NF-kB pathway but further work using other vioprolides and analogues is urgently required. This work will make available samples of vioprolides that will be evaluated for their effects on the activation and moderation of signalling pathways in cells with the interferon mediated pathways and the NF-kB pathway being of immediate interest. This will impact on our understanding of these pathways and how they can be controlled.

The study of the cell signalling pathways will contribute to the development of improved therapies for intractable diseases. By providing vioprolides for further studies, the work outlined in this proposal may help to lead to the development of new therapies and their consequent contribution to the prosperity and success of the UK pharmaceuticals industry.