Synthesis of Antimalarial ICTs Using Biosynthetic Logic

使用生物合成逻辑合成抗疟ICT

• 批准号: 8720792
• 负责人: Ryan Ashok Shenvi
• 金额: $ 35.12万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 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/8720792
• 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; In Vitro; Inhibitory Concentration 50; 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; public health relevance; resistant strain; scaffold; standard of care

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）：本提案的目标是开发新的化学方法，以快速组装结构新颖的ICT抗疟药，并确定其生物学靶标和结构活性关系（SAR）。我们的长期目标是开发新的方法，用于简洁地合成基于铽的药物，这些药物在药物开发方面有着良好的记录，每年的全球市场价值为120亿美元。拟议的研究包括开发一类新的多烯，能够快速多环萜烯合成;一种新的叔醇转化反应;以及将这种化学方法应用于三个ICT亚家族的短，可扩展和模块化合成。这种化学将被用来探索轮廓的ICT结合口袋通过SAR发现和设计光亲和标记的探针，用于识别的ICT大分子目标。研究的第一阶段涉及新的极化树枝状多烯- Danishefsky dendralene-的开发，其经历高度区域和立体选择性的Diels-Alder级联反应，并迅速建立kalihinenes的二环、三环和四环稠合碳环骨架， 两性内酯和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化合物。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氮结合途径的假设。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，这是唯一能够产生的ICT药效团，似乎是一般有用的手性叔烷基胺的合成。与Winzeler小组合作进行的第三阶段研究涉及确定与信通技术抗疟活动有关的作用机制。我们提供了初步数据，表明一种机制，不同于十多年前提出的流行假设。