Total synthesis ad biological evaluation of JBIR-23

人类恶性胸膜间皮瘤（MPM）是一种侵袭性（致命性）肺癌，通常与石棉暴露有关。通常情况下，症状不会出现，直到20-40年后，原来的接触，与预期寿命，然后12-18个月。鉴于石棉在20世纪的广泛使用和如此长的潜伏期，MPM病例继续上升也就不足为奇了。因此，迫切需要开发新的治疗方法来预防MPM，因此开发新的治疗药物至关重要。市场上几乎所有的药物--针对任何症状--都倾向于起源于一种天然产品：那是与自然隔离的东西。不幸的是，目前还没有专门针对间皮瘤的新药。其主要原因是直到最近，还没有天然产物作为先导化合物的报道-这是药物发现过程的起点。2009年，随着JBIR-23和-24的报道，这一情况发生了变化，这两种微生物代谢物分离自链霉菌属AK-AB 27：第一个天然产物，特别是证明对四个MPM细胞系的细胞毒性，该项目的总体目标是研究JBIR-23的首次合成;确认其结构是在其分离时提出的结构;制备JBIR-23的类似物库;最后对这些化合物进行广泛的生物学研究。

Human malignant pleural mesothelioma (MPM) is an aggressive (fatal) lung cancer which is always associated with asbestos exposure. Typically symptoms do not appear until 20-40 years after the original exposure, with life expectancy then 12-18 months. Given the widespread use of asbestos during the 20th century and this long latency period, it is no surprise that cases of MPM continue to rise. Therefore there is an urgent need to develop novel therapeutic approaches for the treatemnt of MPM.Thus the development of new therapeutic agents is crucial. Almost all drugs on the market - for any symptom - tend to have their origins in a natural product: that is something isolated from nature. Unfortunately there are no novel drugs in development specifically targeting mesothelioma. The principle reason for this was that until recently, there were no reported natural products to serve as a lead compound - a starting point for the drug discovery process.This changed in 2009, with the report of JBIR-23 and -24, two microbial metabolites isolated from Streptomyces sp. AK-AB27: the first natural products specifically to demonstrate cytotoxicity against four MPM cell lines, with modest IC50 values of 10-50 uM.The overall aim of the project s to investigate the first synthesis of JBIR-23; to confirm its structure is the one proposed upon its isolation; to prepare a library of analogues of JBIR-23; finally to conduct extensive biological studies on these compounds.