TOTAL SYNTHESIS AND SAR STUDIES OF SALINOSPORAMIDE A

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。蛋白酶体是细胞的垃圾粉碎机，一种吸收受损或寿命短的蛋白质并将其分解以最终处理或回收的酶。当蛋白酶体受到抑制时，蛋白质就不会分解，而是在细胞内堆积起来。这最终是致命的，因为持续的蛋白质降解或“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，比较正常细胞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在对未转化细胞相对无毒的剂量下可以诱导癌细胞死亡。因此，人们对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非常感兴趣。近年来分离到的一种海洋天然产物Salinosporamide A是一种非常有效的选择性蛋白酶体抑制剂，对多种人类癌细胞具有很强的抗癌活性。由于它是最近才被发现的，因此关于赋予所观察到的生物活性的salinosporamide a的结构参数的信息很少。因此，在本研究中，已经开始了salinosporamide a的全合成途径及其随后在详细的构效关系研究中的应用。在迄今为止的研究中，我们已经能够开发出一种新颖而有效的合成途径，以获得对映纯吡咯烷酮-2- 1结构核心，该结构核心含有战略性定位的功能，有望进行进一步的合成转化，以合成所需的天然产物及其各种类似物。本研究的结果将有助于更好地了解盐孢酰胺a的抗癌活性，并有助于实现这种独特化合物作为潜在抗癌治疗剂的巨大潜力。

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.