Generation of multi-functional biological probes based on the anti-inflammatory Tanshinones

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We hypothesise that identifying the molecular target of TIIA will facilitate the development of novel pro-resolution therapeutics for inflammatory disease, which may be more effective than current treatments. In addition, Tanshinones may be useful to trigger apoptosis induced killing of phagocytosed bacteria, making them a potential host-targeted anti-infective agent. We have recently developed a robust synthetic chemical procedure for the gram-scale preparation of a series of Tanshinones, using synthetic chemistry approaches in order to investigate the key functionalities that are required for biological activity. From this we have developed a better understanding of the chemistry design criteria for developing synthetic tanshinones that can incorporate probes to investigate biological function. We will use these to prepare chemically modified 'multi-functional' Tanshinone analogues such that we can label with fluorophores or biotin binders or photoaffinity probes, or a combination of these. This suite of probes will give us the ability to study mechanisms of action of these molecules in more detail using complementary and state of the art imaging technologies. It will also provide a handle to allow us to pull down the biological targets of Tanshinones from neutrophils and identify them by mass spectrometry. This will provide evidence for the mode of action of tanshinones and allow the design of more potent therapeutic agents. The chemical synthesis of these biological probes has significant novelty, while the resulting biological targets will have significant longer term importance.