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

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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.