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Synthesis of Antimalarial ICTs Using Biosynthetic Logic

使用生物合成逻辑合成抗疟ICT

基本信息

批准号：
9066741
负责人：
Ryan Ashok Shenvi
金额：
$ 35.56万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9066741
关键词：
Accounting Alcohols Alder plant Amines Anabolism Antimalarials Artemisinins Binding Biochemical Biogenesis Biological Breathing Carbon Cause of Death Cessation of life Chemicals Chemistry Collaborations Combined Modality Therapy Communities Complex Data Developing Countries Development Drug resistance Environment Exhibits Family Goals Health In Vitro Investigation Ions Laboratories Lead Letters Logic Malaria Marines Marketing Medicine Mefloquine Methodology Methods Nitriles Nitrogen Outcome Parasites Pathway interactions Phase Photoaffinity Labels Plasmodium Polyenes Porifera Public Health Reaction Research Resistance Sea Sesquiterpenes Skeleton Southeastern Asia Structure-Activity Relationship Terpenes analog artemisinine base chemical reaction chemical synthesis cycloaddition design drug development fascinate in vivo mortality novel pharmacophore prevent resistant strain scaffold standard of care

项目摘要

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.

描述（由申请人提供）：该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，并确定其生物靶点和结构活性关系（SAR）。我们的长期目标是开发新方法来简洁合成萜类药物，这些药物在药物开发方面拥有良好的记录，每年占据全球 120 亿美元的市场。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 子族的简短、可扩展和模块化合成。这种化学反应将用于通过 SAR 发现来探索 ICT 结合口袋的轮廓，并设计光亲和标记探针来识别 ICT 大分子目标。研究的第一阶段涉及新型极化树枝状多烯（Danishefsky dendralenes）的开发，它经历高度区域和立体选择性的狄尔斯-阿尔德级联反应，并快速构建 kalihinenes 的二环、三环和四环稠合碳环骨架， amphilectenes 和 adocianes。我们实验室的初步数据表明，这将是一种成功的方法，可广泛应用于其他复杂的碳环。第二阶段的研究从 Scheuer 关于 ICT 生物发生中发现的独特氮结合途径的假设中获得灵感。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，该反应能够独特地生成 ICT 药效团，并且似乎普遍可用于手性叔烷基胺的合成。第三阶段的研究是与 Winzeler 小组合作进行的，涉及确定与 ICT 抗疟活性相关的作用机制。我们提供的初步数据表明了一种与十多年前提出的流行假设不同的机制。