Detailed Information

Synthesis and Application of Pyrimidine-Embedded Polyheterocycles : 피리미딘이 포함된 다중고리골격 화합물들의 합성 및 응용

Cited 0 time in Web of Science Cited 0 time in Scopus


자연과학대학 화학부
Issue Date
서울대학교 대학원
pyrimidinepDOSpolyheterocyclesnon-covalent interactionfluorophore
학위논문 (박사)-- 서울대학교 대학원 : 화학부 유기화학전공, 2016. 8. 박승범.
Identification of new small-molecule modulators is an indispensable research objective in chemical biology and drug discovery. Organic small-molecule library is an inevitable resource in terms of performing the research. To satisfy the unmet need, diversity-oriented synthesis (DOS) has been emerged to maximize skeletal and stereo-chemical diversity of small-molecule library that have high potential to find various functional molecules. On the continuation of DOS strategy research, since 2006 privileged substructure-based DOS (pDOS) strategy has been developed to synthesize privileged structure-containing polyheterocycles with high biological relevancy. Privileged structure is defined as a single molecular framework able to provide high-affinity ligands for more than one type of receptors. Thus, privileged structural motifs have been frequently observed in bioactive natural products and synthetic medicines. Based on the empirical definition, we hypothesized that privileged substructure containing unique and diverse molecular framework serves powerful chemical tools for the identification of new small-molecule modulators. As the beginning of pDOS study, benzopyran embedded pDOS pathway was developed. For last decade, novel bioactive small-molecules have been discovered from the benzopyran pDOS library through a variety of screening campaigns and target identifications. We confirmed the high efficiency of pDOS strategy for identifying new bioactive compounds through the incredible results. In this thesis, development of new pDOS pathways for constructing pyrimidine-containing unprecedented polyheterocycles and their bio-applications toward unexplored biological systems are described.
In Part 1, new synthetic pathways of pyrimidine-containing unprecedented polyheterocycles are introduced. A new diversity-oriented synthesis pathway for the fabrication of a pyrimidine-embedded polyheterocycles library was developed for potential interactions with diverse biopolymers. Five different pyrimidine-embedded molecular frameworks were synthesized from highly functionalized ortho-alkynylpyrimidine carbaldehydes by a silver- or iodine-mediated tandem cyclization strategy. The resulting polyheterocycles possess diverse fused ring sizes and positions with potential functionalities for further modification.
In Part 2, discovery of a new small-molecule to control cellular lipid droplets (LDs) using pyrmidine-containing new aza-tricyclic compounds is described. A series of pyrimidine-embedded polyheterocycles was synthesized using silver- promoted cascade cyclization in a facile manner. The resulting core skeletons containing a unique aza-tricyclic framework allowed for diverse display of non-covalent interacting elements, which probably serve as essentials for perturbing specific non-covalent interactions between various biopolymers. A new small-molecule that decreases the LDs without autophagic activity was discovered by using the unique chemical library.
In Part 3, discovery of new fluorophore and its bioapplication are described. A new fluorescent core skeleton containing pyrazolo[1,5-a]pyridine-fused pyrimidine, named Fluoremidine (FD), was discovered. FD analogues were prepared via a one-pot silver-catalyzed domino cyclization. An N,N-dimethylamino group at the R1- and R2-positions plays important roles in controlling fluorescent brightness and emission wavelength. An N-acetyl group at the R3 position contributes to red shifting of the emission wavelength. FD shows excellent solvatochromism with turn-on fluorescence in the lipophilic environment, which was utilized to design a fluorescent probe, FD13, for visualizing lipid droplets in living cells.
Files in This Item:
Appears in Collections:


Item View & Download Count

  • mendeley

Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.