Synthesis of Antimalarial ICTs Using Biosynthetic Logic

描述(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抗疟疾药物，并确定它们的生物学靶点和结构活性关系(SARS)。我们的长期目标是开发新的方法来简洁地合成以萜类为基础的药物，这种药物在药物开发方面有良好的记录，每年占全球市场120亿美元。拟议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；以及将该化学应用于三个ICT亚家族的短、可扩展和模块化的合成。这一化学将用于通过SAR发现探索ICT结合口袋的轮廓，并设计用于识别ICT大分子靶标的光亲和标记探针。第一阶段的研究涉及开发新的极化树状多烯-丹尼舍夫斯基树状多烯-它经历了高度区域和立体选择性的Diels-Alder级联反应，并迅速建立了卡利希烯的二环、三环和四环稠合碳环骨架， 双链烯和阿多西林。我们实验室的初步数据表明，这将是一种成功的方法，对其他复杂的碳环具有广泛的实用价值。第二阶段的研究灵感来自Scheuer关于ICT生物发生中发现的独特的氮结合途径的假说。我们将探索一种新的化学选择性和立体选择性叔醇转化反应，它是唯一能够产生ICT药效团的反应，似乎对手性叔烷基胺的合成具有普遍意义。与Winzeler小组合作进行的第三阶段研究涉及确定与信通技术的抗疟疾活动有关的行动机制。我们提供的初步数据表明，一种与十多年前提出的流行假说不同的机制。

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.