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Dynamic Synthesis of Drug-Candidate Molecules Utilizing Cooperative Effect of Integrated Functional Groups

利用集成官能团的协同作用动态合成候选药物分子

基本信息

批准号：
18390039
负责人：
HIGUCHI Tsunehiko
金额：
$ 9.96万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Dynamic combinatorial chemistry (DCC) is a new approach to integration of combinatorial synthesis and screening based on the shift of chemical equilibrium in a mixture of interconverting components driven by a molecular target. We have designed a new DCC scaffold (BB-4) that has three formyl groups to condense with various amines reversibly at the same side of the benzene ring. N-Ac-L-Ile and N-Ac -Ile-Ala, which are key parts in amyloid β42 for aggregation of amyloid β42 were selected because a good receptors for these compounds can be potential drug for Alzheimer disease.Equilibration of the scaffold with a mixture of amines was expected to produce imines, the distribution of which would be altered by the addition of N-Ac-L-Ile or N-Ac -Ile-Ala. The imines were then reduced to the secondary amines, the composition of which was analyzed LC/FT-MS. Clearly, addition of the molecular target resulted in dramatic amplification of selected amine peaks. Most amplified compound was 9c of which affinity with N-Ac-L-Ile was relatively high; the binding constant is 0.96 x 10^3 M^<-1>. The present strategy for preparation of low-molecular-weight receptors would be applicable to various molecular targets.A new Mn (salen) complex bearing an ureido group as an auxiliary that is three-dimensionally fixed by a cyclopentane ring fused to the salen structure was developed. This compound exhibited considerably higher catalase-like activity than the original Mn(salen), i.e., the cyclopentane-fused Mn (salen) without the auxiliary, under near-physiological conditions.

动态组合化学（DCC）是一种新的组合合成和筛选的集成方法，它基于分子靶点驱动的相互转化组分混合物中化学平衡的移动。我们设计了一种新的DCC支架（BB-4），它具有三个甲酰基，可以在苯环的同一侧可逆地与各种胺缩合。N-Ac-L-Ile和N-Ac -Ile-Ala是淀粉样蛋白β 42聚集的关键部位，它们是治疗阿尔茨海默病的潜在药物，而N-Ac-L-Ile和N-Ac -Ile-Ala的加入可以改变亚胺的分布。然后将亚胺还原为仲胺，通过LC/FT-MS分析其组成。显然，添加分子靶标导致所选胺峰的显著放大。扩增最多的化合物是9 c，其与N-Ac-L-Ile的亲和力相对较高;结合常数为0.96 x 10^3 M^<-1>。本研究设计并合成了一种以脲基为辅助基团的新型Mn（salen）配合物，该配合物通过环戊烷环与salen结构形成三维立体结构，并通过配体的作用将脲基固定在salen结构上。该化合物表现出比原始Mn（salen）高得多的过氧化氢酶样活性，即，环戊烷稠合的Mn（salen）在无助剂的情况下，在接近生理条件下。