Diversity-oriented synthesis of natural product analogs and development of lead candidates for anti-infectious agents

天然产物类似物的多样性合成和抗感染药物先导候选物的开发

基本信息

批准号：
19681022
负责人：
OGURI Hiroki
金额：
$ 15.48万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (A)
财政年份：
2007
资助国家：
日本
起止时间：
2007 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19681022/
关键词：
生理活性分子の設計・合成天然物多様性指向型合成化合物ライブラリートリパノソーママラリア構造多様性リード化合物アルテミシニン天然物アナログ低分子プローブ熱帯感染症短段階合成低分子プロープ天然物類似低分子感染症オレフィンメタセシス

项目摘要

To access high-quality small molecule libraries to screen lead candidates for neglected diseases exemplified by human African trypanosomiasis, we sought to develop a synthetic process that would produce collections of cyclic scaffolds relevant to an assortment of natural products exhibiting desirable biological activities. By extracting the common structural features among several sesquiterpenes including artemisinin, anthecularin and transtaganolides, we designed six types of scaffolds with systematic structural variations consisting of (i) three types of stereochemical relationships on the sp^3 ring-junctions and (ii) two distinct arrays of tricyclic frameworks. Amodular and stereo-divergent assembly of dienynes exploiting a versatile manifold produced a series of cyclization precursors. Divergent cyclizations of the dienynes employing tandem ring-closing metathesis reactions overrode variant reactivities of the cyclization precursors leading to the six canonical sets of the tricyclic scaffolds incorporating a diene group. Screenings of trypanosomal activities of the canonical sets, as well as regio- and stereoisomers of the tricyclic dienes, allowed generation of several anti-trypanosomal agents defining the three-dimensional shape of the pharmacophore. The candidate tricyclic dienes were selected by primary screenings and further subjected to installation of a peroxide bridge, which generated artemisinin analogs that exhibited potent in vitro anti-trypanosomal activities comparable or even superior to those of artemisinin and approved drugs, suramin and eflornithine.

为了访问高质量的小分子文库，以筛选铅候选者的忽视疾病，以人类非洲锥虫病为例，我们试图开发一种合成过程，该过程将产生与各种自然产品相关的环状支架的集合。通过在几种倍半萜烯中提取常见的结构特征，包括青蒿素，动脉粥样硬化和transtaganolides，我们设计了六种类型的脚手架，具有系统的结构变化，包括（i）在SP^3环形界面上的三种立体化学关系，以及（II）两种不同的三环形框架阵列。利用多功能歧管的二尼尼球体的肌和立体异常组装产生了一系列的环化前体。使用串联环的分解反应反应的二烯二烯二烯的不同循环反应覆盖了六个构成二烯基团的三轮车支架的六个规范组的环体的反应性。筛选规范组的锥虫活性，以及三环二烯的区域和立体异构体，允许生成几种定义药理三维形状的几种抗肌体剂。通过初次筛选选择候选三环二烯，并进一步安装过氧化桥，该桥产生了青蒿素类似物，这些类似物表现出有效的体外抗肌体活动，甚至可以与Artemisinin和Artemisinin and Suramin and Eflornithine相当甚至优越。