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）：该提案的目的是开发新的化学方法来快速组装结构新颖的ICT抗疟药，并确定其生物学靶标和结构活动关系（SARS）。我们的长期目标是开发新的方法来简化基于萜烯的药物，这些药物在药物开发方面具有良好的田径记录，并占全球120亿美元的全球市场。拟议的研究包括能够快速多循环萜烯合成的新型多烯的开发。一种新的Tert-Ter-Alochol反应反应；并将这种化学的应用于三个ICT亚家族的短，可扩展和模块化合成。该化学将通过SAR发现来探索ICT结合口袋的轮廓，并设计具有光性标记的探针，以鉴定ICT大分子靶标。研究的第一阶段涉及新的极化树突多烯的发展-Danishefsky dendralenes，其经历了高度的区域和立体选择性的Diels-Alder-Alder cascade反应，并迅速累积了di-，tri-and tracyclic融合型碳纤维骨骼骨骼的di-，tri-ti-ti-ti-ti-ti-ti-ti-ti-ti-ti-di-dendrenes。两栖苯甲酸酯和adocianes。来自我们实验室的初步数据表明，这将是一种成功的方法，可以广泛使用其他复杂的碳循环。研究的第二阶段从Scheuer关于在ICT生物发生中发现的独特氮的假设中获得了灵感。我们将探索一种新的化学选择性和立体选择性的Tert-Tert-Chochol反应反应，该反应具有独特的能力产生ICT药片基团，并且似乎对于合成手性Tert-Tert-Alkyl胺的合成通常很有用。与Winzeler组合作进行的研究的第三阶段涉及确定与ICT抗疟疾活性相关的作用机理。我们提供了初步数据，该数据表明一种机制与十年前的普遍假设不同。