TOTAL SYNTHESIS AND SAR STUDIES OF SALINOSPORAMIDE A

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 蛋白酶体是细胞的垃圾粉碎机，是一种酶，它吸收受损或短暂的蛋白质，并将其分解，以供最终处理或回收。当蛋白酶体被抑制时，蛋白质不是在细胞内分解，而是在细胞内积聚。这最终是致命的，因为持续的蛋白质降解或‘周转’对于正常的细胞功能是必要的。有趣的是，恶性细胞对蛋白酶体活性的丧失更敏感，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。人们还发现，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型抗癌药物的可能性引起了极大的兴趣。新近分离的海洋天然产物盐孢酰胺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具有很强的抗癌活性。由于其最近的发现，关于赋予盐孢酰胺A观察到的生物活性的结构参数的信息很少。因此，在本研究中，盐孢酰胺A的全合成路线及其随后的应用被用于详细的构效关系研究。在到目前为止的研究中，我们已经能够开发出一种新颖而有效的合成路线来合成对映体吡咯烷酮-2-酮结构核心，该结构核心包含具有战略位置的官能团，有望允许进一步的合成转化，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提供更好的了解是什么赋予盐孢子酰胺A的抗癌活性，并帮助实现这种独特的化合物在最终开发为潜在的抗癌治疗剂方面的巨大希望。

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.