Privileged Structures: Efficient Chemical 鈥淣avigators鈥?toward Unexplored Biologically Relevant Chemical Spaces
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- 作者：Jonghoon Kim ; Heejun Kim ; Seung Bum Park
- 刊名：Journal of the American Chemical Society
- 出版年：2014
- 出版时间：October 22, 2014
- 年：2014
- 卷：136
- 期：42
- 页码：14629-14638
- 全文大小：651K
- ISSN：1520-5126
文摘
In the search for new therapeutic agents for currently incurable diseases, attention has turned to traditionally 鈥渦ndruggable鈥?targets, and collections of drug-like small molecules with high diversity and quality have become a prerequisite for new breakthroughs. To generate such collections, the diversity-oriented synthesis (DOS) strategy was developed, which aims to populate new chemical space with drug-like compounds containing a high degree of molecular diversity. The resulting DOS-derived libraries have been of great value for the discovery of various bioactive small molecules and therapeutic agents, and thus DOS has emerged as an essential tool in chemical biology and drug discovery. However, the key challenge has become how to design and synthesize drug-like small-molecule libraries with improved biological relevancy as well as maximum molecular diversity. This Perspective presents the development of privileged substructure-based DOS (pDOS), an efficient strategy for the construction of polyheterocyclic compound libraries with high biological relevancy. We envisioned the specific interaction of drug-like small molecules with certain biopolymers via the incorporation of privileged substructures into polyheterocyclic core skeletons. The importance of privileged substructures such as benzopyran, pyrimidine, and oxopiperazine in rigid skeletons was clearly demonstrated through the discovery of bioactive small molecules and the subsequent identification of appropriate target biomolecule using a method called 鈥渇luorescence difference in two-dimensional gel electrophoresis鈥? Focusing on examples of pDOS-derived bioactive compounds with exceptional specificity, we discuss the capability of privileged structures to serve as chemical 鈥渘avigators鈥?toward biologically relevant chemical spaces. We also provide an outlook on chemical biology research and drug discovery using biologically relevant compound libraries constructed by pDOS, biology-oriented synthesis, or natural product-inspired DOS.