TOTAL SYNTHESIS AND SAR STUDIES OF SALINOSPORAMIDE A

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 蛋白酶体是细胞的垃圾粉碎机，这种酶吸收受损或寿命短的蛋白质，并将它们分解，以便最终处理或回收。当蛋白酶体被抑制时，蛋白质不是分解，而是在细胞中积累。这最终是致命的，因为恒定的蛋白质降解或“周转”是正常细胞功能所必需的。有趣的是，恶性细胞对蛋白酶体活性的丧失更敏感，并且比较正常和恶性细胞的研究表明，蛋白酶体抑制使恶性细胞对凋亡或程序性细胞死亡敏感。还发现蛋白酶体抑制剂可以在对未转化细胞相对无毒的剂量下诱导癌细胞死亡。因此，蛋白酶体抑制剂可能被证明是有用的新的抗癌剂的可能性，有很大的兴趣。最近分离的海洋天然产物Salinosporamide A被发现是一种非常有效和选择性的蛋白酶体抑制剂，并且对多种人类癌细胞系也表现出高效的抗癌活性。由于其最近的发现，非常少的信息是有关的结构参数，赋予所观察到的生物活性的盐孢菌酰胺A。因此，在本研究中，salinosporamide A的全合成路线及其随后的应用对详细的构效关系的调查已经开始。在到目前为止的研究中，我们已经能够开发一种新的和有效的合成路线，以获得对映体纯的吡咯烷-2-酮结构核心，其含有预期允许进一步合成转化的策略性定位的官能团，以合成所需的天然产物及其各种类似物。预计这项研究的结果将更好地了解是什么赋予salinosporamide A抗癌活性，并有助于实现这种独特化合物作为潜在抗癌治疗剂的最终发展前景。

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.