Synthetic studies on the small molecule tool (S)-(-)-blebbistatin
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Small molecules that can perturb the function of a specific target protein are useful tools in basic cell biology research. Important areas in biology, such as cytokinesis (the last step in cell division), have not been extensively explored due to the lack of suitable small molecule tools that target their relevant proteins. Non-muscle myosin II has been identified as a protein component necessary for cell division. A recent programme focused on identifying novel inhibitors of non-muscle myosin II has been developed at Harvard University and screening of a commercially available compound library led to the discovery of the novel small molecule inhibitor, (-)-blebbistatin. This thesis describes an efficient and flexible synthetic approach to highly optically enriched (-)-blebbistatin. The bioactive compound is synthesised from 2-amino-5-methylbenzoic acid in a four step procedure. The key step is the asymmetric hydroxylation of a quinolone intermediate using the Davis oxaziridine methodology. For the first time, we have proved that the absolute stereochemistry of (-)-blebbistatin is S by X-ray analysis of a heavy atom containing analogue of blebbistatin. Subsequent studies on the core structure of blebbistatin show that it is possible through chemical modification to prepare analogues. Further biological testing of these compounds show which parts of (S)-(-)-blebbistatin are important to retain its inhibitory activity. In addition, it is shown that the incorporation of a nitro functional group into the blebbistatin core structure modifies its fluorescence properties. This is of importance since this analogue can therefore be used in fluorescence-based microscope imaging experiments on live cells where (-)-blebbistatin cannot.
Thesis, PhD Doctor of Philosopy
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