KCS

Diversity-oriented synthesis (DOS), which aims to populate the chemical space with skeletally and stereochemically diverse small molecules with high appending potentials, has been proven to be an essential tool for the discovery of bioactive small molecules. The incorporation of privileged substructural motifs became an essential element in DOS pathways. Multistep, practical solid-phase strategies for the synthesis of benzopyran-embedded polyheterocycles and natural product-like diaza-bridged heterocycles have been developed. These synthetic pathways were established through the divergent approach from unique key intermediates. In addition, we constructed various drug-like small molecule library containing novel molecular frameworks embedded with privileged substructures such as benzodiazepine, pyrazole, pyrazolopyrimidine, and pyrimidine. The each key step was regioselective and diastereoselective to provide final products as single diastereomers in exceptional yields and purities without further purification, which was confirmed by NMR structural study and LC/MS analysis. In this presentation, I would like to share the current approach for the discovery of novel therapeutic agents using molecular diversity constructed by our DOS exercise along with chemical biology approach. The various high throughput screening revealed the biological activities of synthetic small molecules along with their potential applications as new therapeutic agents. We also confirmed their biological activities in animal models. Finally, I would like to introduce our effort on the target validation using PACID technology with 2D gel electrophoresis.