Synthesis of Antimalarial ICTs Using Biosynthetic Logic

描述（由申请人提供）：本提案的目标是开发新的化学方法来快速组装结构新颖的ICT抗疟药物，并确定其生物靶点和结构活性关系（SARs）。我们的长期目标是开发以萜烯为基础的药物的简明合成新方法，萜烯类药物在药物开发方面有良好的记录，每年占120亿美元的全球市场。拟进行的研究包括：开发一类能够快速合成多环萜烯的新型多烯；一种新的叔醇转化反应以及将这种化学物质应用于三个ICT亚族的短时间、可扩展和模块化合成。该化学将通过SAR发现来探索ICT结合袋的轮廓，并设计用于识别ICT大分子靶标的光亲和标记探针。第一阶段的研究是开发新的极化树突多烯-丹尼谢夫斯基树突多烯-它经过高度的区域和立体选择性diols - alder级联反应，并迅速建立二环，三环和四环融合碳环骨架。

DESCRIPTION (provided by applicant): The goal of this proposal is to develop new chemical methods to rapidly assemble the structurally novel ICT antimalarials, and determine their biological target and structure activity relationships (SARs). Our long-term goal is to develop new methods for the concise synthesis of terpene-based medicines, which have a proven track-record in drug development and account for an annual $12 billion global market. The proposed research comprises the development of a new class of polyene capable of rapid polycyclic terpene synthesis; a new tert-alcohol inversion reaction; and application of this chemistry to short, scalable and modular syntheses of three ICT subfamilies. This chemistry will be used to explore the contours of the ICT binding pocket through SAR discovery and to design photoaffinity labeled probes for identification of the ICT macromolecular target. The first phase of research concerns the development of new polarized dendritic polyenes - Danishefsky dendralenes - which undergo highly regio- and stereoselective Diels-Alder cascade reactions and rapidly build up the di-, tri-, and tetracyclic fused carbocyclic skeletons of the kalihinenes, amphilectenes, and adocianes. Preliminary data from our laboratory indicates that this will be a successful approach with widespread utility to other complex carbocycles. The second phase of research derives inspiration from Scheuer's hypothesis regarding the unique nitrogen incorporating pathways found in ICT biogenesis. We will explore a new chemoselective and stereoselective tert-alcohol inversion reaction, which is uniquely capable of generating the ICT pharmacophore and appears to be generally useful for the synthesis of chiral tert-alkyl amines. The third phase of research, conducted in collaboration with the Winzeler group, involves determination of the mechanism of action associated with the antimalarial activity of the ICTs. We provide preliminary data suggesting a mechanism that differs from the prevailing hypothesis put forth over a decade ago.