Development of novel Pyrimidine-Embedded Polyheterocycles and Privileged Tetra-Substituted tetrahydro-1H-pyrazino[2,1-c][1,2,4]triazine-4,7(6H,8H)-dione library using Privileged Substructure-Based Diversity-Oriented Synthesis (pDOS)

Abstract

Small molecule libraries play a crucial role in chemical biology, especially, in high-throughput screening. It leads to discovery of new hit to lead compound that potential application in clinical phase. Therefore, library construction strategy is a subject for organic chemist. One of the most famous and important trend is Diversity-oriented Synthesis (DOS) methodology, which was developed by Professor Stuart Schreiber. From the first time introduced, DOS has been proved to be an essential tool in the exploration of chemical and biological space. Our research group has been working on the development of new DOS pathways and library realizations, we proposed a privileged substructure-based diversity-oriented synthesis (pDOS) approach for the efficient generation of distinct polyheterocyclic core skeletons embedded with privileged structure. Continuation of our work, we using pDOS approach for development of new pDOS pathways and construction of small compound libraries for high-throughput screening.

In chapter 1, a new privileged substructure-based diversity-oriented synthesis (pDOS) pathway for the systematic fabrication of polyheterocyclic molecular frameworks with pyrimidine as the key privileged substructure ring have been developed. In this study, we established five pathways to achieve different pyrimidine-embedded core skeletons from a key intermediate ortho-alkynylpyrimidine carbaldehydes with high molecular diversity and positions with potential functionalities for further modification. In chapter 2, we describe the practical construction of library using solid-phase synthesis with Tetra-Substituted tetrahydro-1H-pyrazino[2,1-c][1,2,4]triazine-4,7(6H,8H)-dione as the core privileged substructure. The diversity of this core skeleton was expanded by introduction of at four R- substituted diversity points. As a result, 81 compound libraries were constructed with provide a potential source of for biological screening.