Synthesis of Bioactive Substances

这项提议的第一个目标是设计和合成新的抗疟疾药物。最近有报道称，manzamine A是一种高效的抗疟药，这使得manzamine相关结构的合成和生物学评价成为医学上的一个重要目标。本文描述了与沃尔特里德陆军研究所（WRAIR）的David Skanchey博士合作的简单曼扎胺类似物的合成和这些结构的生物学评价。Winkler实验室为首次全合成manzamine A而开发的方法将用于构建这些新的抗疟疾候选药物。该提案的第二个目标是完成第一次全合成ingenol，这是一种天然存在的二萜，是普遍存在的细胞信号系统蛋白激酶C （PKC）的有效激活剂。鉴于PKC激活剂诱导的生物反应，该酶抑制剂的开发可能会导致治疗慢性炎症和增生性疾病的药物。迄今为止，尽管世界各地的实验室都在努力，ingenol还没有完全合成。Winkler实验室开发的分子内二恶英酮反应提供了一种独特的方法来控制构建ingenol的关键内外立体化学关系。结合Winkler实验室的文献先例和进展报告中描述的未发表的结果，应该会导致在拟议的项目期间完成第一个ingenol的全合成。

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 The combination of literature precedent from the Winkler laboratory with the unpublished results described in the Progress Report should lead to the completion of the first total synthesis of ingenol during the proposed project period.