Chemical Genetics/Genomics Approach for Drug Discovery Process

다국어 초록 (Multilingual Abstract)

A multistep, practical solid-phase strategy for the synthesis of natural product-like diaza-bridged heterocycles was developed. A key step in the library synthesis is tandem acidolytic cleavage with subsequent in situ iminium formation followed by the Pictet-Spengler intramolecular cyclization. The Pictet-Spengler type intramolecular cyclization step was regioselective and diastereoselective to give final products as single diastereomers in exceptional yields and purities, which was confirmed by NMR structural study and LC/MS analysis. This approach is exemplified by the preparation of a 384-member library of 3,9-diazabicyclo[3.3.1]non-6-en-2-one skeletons, fused with indole and dihydroxybenzene and diversified at two bridging nitrogen atoms, using the solid-phase parallel synthetic methodology without further purification. In this pilot library, two diastereomerically enriched diaza-bridged core skeletons were modified by amide and urea bond formation on bridging nitrogen atoms and this scheme exhibits the potential for expansion in order to obtain fin1her diversification. The biological evaluation of these compounds were pursued in the AMP-activated Protein Kinase(AMPK) Pathway, which is the key regulatory system of energy expenditure in cells and might be important in the development of metabolic diseases, such as type 2 diabetes and obesity. The initial screening by the fluctuation of NAD(P)H levels in cells yielded a series of compounds from this library, and the western blot showed that several compounds domonstrates the activation of AMPK by specific phosphorylation of Thr 172 on catalytic alpha subunit in heterotrimeric complex. Based on the preliminary structure-activity relationship study, the focused library construction and the mechanistic study of AMPK activation process are currently underway.