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

动态组合化学(DCC)是一种基于分子靶标驱动的相互转化组分的化学平衡发生变化的组合合成和筛选一体化的新方法。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与各种胺进行可逆缩合。N-Ac-L-Ile和N-Ac-Ile-Ala是淀粉样蛋白β42中聚集淀粉样蛋白β42的关键成分，是因为这些化合物的良好受体可能成为治疗阿尔茨海默病的潜在药物。用胺混合物平衡支架有望产生亚胺，添加N-Ac-L-Ile或N-Ac-Ile-Ala将改变亚胺的分布。然后将亚胺还原为仲胺，并对其组成进行LC/FT-MS分析。显然，分子靶标的加入导致了选定的胺峰的显著放大。扩增产物以9c为主，与N-Ac-L-Ile亲和力较高，结合常数为0.96×10~(-3)M^~(-1)~(-1)。目前制备低分子质量受体的策略将适用于各种分子靶标。开发了一种新的以缩脲基团为辅助的、通过与Salen结构融合的环戊烷环三维固定的Mn(Salen)配合物。在近生理条件下，该化合物的过氧化氢酶活性明显高于原Mn(Salen)，即无辅助剂的环戊烷熔融Mn(Salen)。

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.