TOTAL SYNTHESIS AND SAR STUDIES OF SALINOSPORAMIDE A

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proteasome is the cell's garbage shredder, an enzyme that sucks in damaged or short-lived proteins and dismembers them for eventual disposal or recycling. When proteasome is inhibited, proteins, instead of disintegrating, build up in the cell. This is ultimately fatal, because constant protein degradation or 'turnover' is necessary for proper cell function. Interestingly, malignant cells are more sensitive to the loss of proteasome activity, and studies comparing normal and malignant cells have shown that proteasome inhibition sensitizes malignant cells to apoptosis or programmed cell death. It has also been seen that proteasome inhibitors can induce cancer cell death at doses that are comparatively non-toxic to untransformed cells. There has therefore been a great deal of interest in the possibility that proteasome inhibitors might prove useful as novel anticancer agents. A recently isolated marine natural product, Salinosporamide A, was found to be a very efficient and selective inhibitor of proteasome and also exhibited highly potent anticancer activity against a variety of human cancer cell lines. Because of its recent discovery, very little information is available about the structural parameters that impart the observed biological activity to salinosporamide A. Therefore, in the present research, a total synthetic route to salinosporamide A and its subsequent application towards a detailed structure-activity relationship investigation have been initiated. In studies so far, we have been able to develop a novel and efficient synthetic route to an enantiopure pyrrolidin-2-one structural core, containing strategically located functionalities that are expected to allow further synthetic transformations, towards synthesizing the desired natural product and various analogs thereof. It is expected that results from this research will provide a better understanding of what imparts anticancer activity to salinosporamide A, and help realize the high promise of this unique compound in its ultimate development as a potential anticancer therapeutic agent.