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Development of Synthetic Pathways for Bioactive Small Molecules as Exploring Tools for Biological System: Molecular Diversity-Based Approach and Protein Structure-Based Approach : 생명 현상 연구를 위한 생리 활성을 가지는 저분자 화합물들의 합성 경로 개발: 분자 다양성 기반 접근 방법 및 단백질 구조 기반 접근 방법
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- Authors
- Advisor
- 박승범
- Major
- 자연과학대학 화학부
- Issue Date
- 2016-08
- Publisher
- 서울대학교 대학원
- Keywords
- bioactive small molecule ; molecular diversity ; privileged structure ; regioselective synthesis ; tetrahydroindazolone ; chemical library ; solid-phase reagent ; solid-phase synthesis ; natural killer T cell ; CD1d ; alpha-galactosylceramide ; rational design ; noncovalent interaction ; covalent interaction ; Bacteroid fragilis ; glycosphingolipid ; symbiotic bacteria
- Description
- 학위논문 (박사)-- 서울대학교 대학원 : 화학부 유기화학전공, 2016. 8. 박승범.
- Abstract
- Curiosity about biological system is a fundamental topics of science. Since the landmark description of DNA double helix by Watson and Crick, our understanding about biological processes from DNA to protein, so called central dogma, has been expanding greatly. Various genetic technics, such as genetic mutagenesis, transgenic, knockout, and knockin, have been used as research tools for exploring biological system. In addition to classic genetics, chemical genetics has emerged as a complementary approach in biological study. In a broad sense, chemical genetics mean the biological study using small molecules interacting with biological component. So the discovery of bioactive small molecules is the essential prerequisite for the success of chemical genetic approach. In this context, I have being studies about the design and synthesis of (potential) bioactive small molecules for studying biological system.
There are two cases in discovering bioactive small molecules. The one is the case that novel small molecules are needed to be discovered without biased biological target. In this situation, molecular diversity of synthetic small molecules is crucial to covered wide range of chemical space. And the other case is when the information about the target biological component is available, for example X-ray crystal structure of target protein with/without their ligand. In this case, rational design of small molecules based on the structural information of biological component is possible.
In part I, the researches about the development of synthetic pathway and its application for small molecule library construction to discover new biological small molecule were introduced as molecular diversity-based approach. As chapter I, from the selection of tetrahydroindazolone as core structure using privileged structure concept to the development of orthogonal regioselective synthetic pathway for complementary both regioiosmers were achieved. And the efficient synthetic approaches to construct chemical library of tetrahydroindazolone in solution phase/solid phase were studied in chapter 2 and chapter 3.
In part II, the story about the rational design of bioactive small molecules and its derivatives based on the crystal structure of target protein and its ligand and the development of synthetic pathways were described as protein structure-based approach. Especially, the interaction between invariant natural killer T (iNKT) cell, playing a pivotal role in immune system, and its ligand α-galactosylceramide (α-GalCer) was major research interest. In chapter I, from design and synthesis of α-GalCer analogs perturbing non-covalent interaction with its receptor protein to validation of its therapeutic potential for animal model was studied. And in chapter 2, new α-GalCer analogs were designed to modulate the interaction with its receptor as covalently and efficient synthetic pathway was also developed. Lastly, the synthetic pathway for endogenous α-GalCer of Bacteroid fragilis and its analogs was developed for the research of host-symbiotic bacteria interaction in immune system.
- Language
- Korean
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