Synthesis of Bioactive Substances

该提案的第一个目标是设计和合成新型抗疟药物。最近有报道，manzamine A是一种高效的抗疟疾剂，使得manzamine相关结构的合成和生物学评价成为医学中的重要目标。简单的manzamine类似物的合成和生物学评价，这些结构的合作与博士大卫Skanchey在沃尔特里德陆军研究所（WRAIR）的描述。在Winkler实验室开发的第一个全合成manzamine A的方法将用于构建这些新型抗疟疾候选药物。该提案的第二个目标是完成巨大戟二萜醇的首次全合成，巨大戟二萜醇是一种天然存在的二萜，是普遍存在的细胞信号传导系统蛋白激酶C（PKC）的有效激活剂。考虑到PKC激活剂诱导的生物反应，这种酶的抑制剂的开发可能导致可用于治疗慢性炎性和增殖性疾病的治疗剂。到目前为止，尽管世界各地的实验室做出了努力，但巨大戟醇尚未实现全合成。Winkler实验室开发的分子内二恶烯酮反应提供了一种独特的方法来控制巨大戟二萜醇构建中关键的内外立体化学关系。温克勒实验室的文献先例与进展报告中描述的未发表结果相结合，应能在拟议项目期间完成巨大戟醇的首次全合成。

The first goal of this proposal is the design and synthesis of novel antimalarial drugs. It has recently been reported that manzamine A is a highly potent antimalarial agent, making the synthesis and biological evaluation of manzamine-related structures an important goal in medicine. The synthesis of simple manzamine analogs and the biological evaluation of these structures in collaboration with Dr. David Skanchey at the Walter Reed Army Institute of Research (WRAIR) is described. The methodology that was developed in the Winkler laboratory for the first total synthesis of manzamine A will be used in the construction of these novel antimalarial drug candidates. The second goal of this proposal is the completion of the first total synthesis of ingenol, a naturally occurring diterpene that is a potent activator of the ubiquitous cell signaling system protein kinase C (PKC). Given the biological responses induced by activators of PKC, the development of inhibitors of this enzyme may lead to therapeutic agents useful in the treatment of chronic inflammatory and proliferative diseases. To date, ingenol has not yet yielded to total synthesis, despite the efforts of laboratories around the world. The intramolecular dioxenone reaction developed in the Winkler laboratory provides a unique approach to the control of the critical inside-outside stereochemical relationship in the construction of ingenol. The combination of literature precedent from the Winkler laboratory with the unpublished results described in the Progress Report should lead to the completion of the first total synthesis of ingenol during the proposed project period.