Total syntheses of vioprolides for further biological evaluation

人类细胞有各种各样的过程来保护自己免受细菌和病毒感染。其中一些过程是由信号通路介导的，这些信号通路警告细胞受到威胁并启动反应。干扰素介导的途径对于细胞防御是必不可少的。NF-kB通路与炎症有关，特别是与人类慢性炎症性肠病有关。这些途径可以受到一系列“小”分子的影响，并且研究这些化合物如何激活或调节这些途径在更彻底地理解它们的背景下以及随着一系列病毒和炎性疾病的新疗法的开发而具有相当大的兴趣。Vioprolides是一组从粘细菌中分离的修饰的环肽，已显示其对细胞中干扰素介导的途径具有协同活化作用，并对NF-κ B途径具有调节作用。不幸的是，可从天然来源获得的Vioprolides的量确实非常有限，并且限制了对这些化合物的生物学效应的进一步研究。建议从更简单的市售化合物中开发这些vioprolides的合成方法，以便恢复生物学研究。此外，一旦这些合成完成，应该可以对其进行修饰以提供天然存在的化合物的类似物，以便研究结构变化对这些化合物的生物活性的影响。这些合成本身将是具有挑战性的，尽管通过使用收敛方法，希望最长的线性路线将不超过20步。合成不会是直接的，因为嵌入在vioprolides的结构中的是使它们对某些化学试剂非常敏感的特征。然而，根据初步研究，已经提出了一种处理这些化合物的方法，并将成为在该赠款支持下开展的工作的基础。最后，应该注意的是，Vioprolides在纳克水平上具有活性。因此，尽管它希望至少能制备出一种百毫克规模的维奥普列，但数十毫克的合成量应该为生物学研究的继续提供了足够的材料。

Human cells have various processes to protect themselves from bacterial and viral infections. Some of these processes are mediated by signalling pathways that alert the cell to a threat and initiate a response. Interferon mediated pathways are essential for cell defence. The NF-kB pathway is linked to inflammation and specifically to chronic inflammatory bowel disease in humans. These pathways can be influenced by a range of "small" molecules and the study of how such compounds can activate or moderate these pathways is of considerable interest in the context of understanding them more thoroughly and with the development of new therapies for a range of viral and inflammatory diseases. The vioprolides are a group of modified cyclic peptides isolated from a myxobacterium that have been shown to have a synergystic activating effect on an interferon mediated pathway in cells and a moderating effect on the NF-kB pathway. Unfortunately the quantities of vioprolides that are available from the natural source are very limited indeed and are restricting further studies into the biological effects of these compounds. It is proposed to develop syntheses of these vioprolides from simpler commercially available compounds so that the biological studies can be resumed. Moreover once these syntheses are complete, it should be possible to modify them to provide analogues of the naturally occurring compounds in order to study aspects of the effects of structural changes on the biological activities of these compounds. These syntheses will be challenging in themselves although by using a convergent approach it is hoped that the longest linear route will be no more than 20 steps long. The syntheses will not be straight forward since embedded within the structures of the vioprolides are features that made them very sensitive to certain chemical reagents. However, based on preliminary studies an approach to these compounds has been put forward and will be the basis of the work to be carried out with the support of this grant. Finally, it should be noted that the vioprolides are active at the nanogramme level. So the synthesis of tens of milligramme quantities should provide enough material for biological studies to continue although it it hoped to prepare at least one vioprolide on a hundred milligramme scale.