트랜스-옥사졸리딘 메틸 에스터 신톤의 응용을 통한 가능한 아미노펩티다아제 억제제들의 입체선택적인 합성

학위논문 (석사)-- 서울대학교 대학원 : 화학생물공학부, 2015. 8. 김영규.Aminopeptidases are enzymes that catalyze the hydrolytic cleavage of peptides from the N-terminus of amino acid or peptide substrates. It is widely distributed over the human, the animal and the plants, and are essential materials for protein maturation, activation and regulation of (non-)hormonal peptides. Aminopeptidase inhibitors suppress aminopeptidases activity so that prevent undesired replication of viruses or cells such as tumor. Ubenimex, commercial name of Bestatin, is one of aminopeptidase inhibitor which is marketed as treatment of acute myelocytic leukemia. Several stereoselective total syntheses of bestatin and its derivatives such as 2-thiolbestatin or bestatin thioamide have been reported. Most of bestatin analogs which have been reported contain aryl group at the N-terminus, but in this thesis, aryl group is substituted with isobutyl group or isopropyl group. Synthesis of new bestatin derivatives have been studied with two kinds of chiral synthons from D-leucine and D-valine. The precursors for corresponding β-amino-α-hydroxy acids were prepared via intramolecular conjugate addition between phenylsulfonylnitromethane and N-hydroxymethyl protected α-amino aldehydes. Bestatin derivatives which contain isobutyl group, (2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl-L-leucine or isopropyl group, (2S,3R)-3-amino-2-hydroxy-4-methylpentanoyl-L-leucine are synthesized with peptide coupling between corresponding β-amino-α-hydroxy acids and L-Leu-OMe. Lapstatin, 3-amino-2-hydroxy-4-methylpentanoyl-valine, is one of aminopeptidase inhibitors which has similar vicinal amino alcohol structure to synthesized bestatin derivatives. But, lapstatin has not been fully identified its stereochemistry of the vicinal amino alcohol at the N-terminal amino acid residue, while the structure of bestatin derivatives were well established. Employing the developed synthetic method, lapstatin derivatives are also synthesized from corresponding β-amino-α-hydroxy acids in order to confirm its stereochemistry.ABSTRACT....................................................................................i LIST OF FIGURES.........................................................................v LIST OF SCHEMES......................................................................vi LIST OF ABBREVIATIONS.........................................................vii 1. Introduction...........................................................................1 1.1. Aminopeptidase inhibitors......................................................1 1.2. Reported synthetic method for threo-β-amino-α-hydroxy acid...........................................4 2. Background for the present study........................................8 2.1. N,O-Acetal lactols derived from α-amino acids....................8 2.2. Stereoselective synthesis of threo-β-amino-α-hydroxy acids.........................................9 2.3. Synthetic plans for derivatives of aminopeptidase inhibitors....................................................11 3. Results and Discussion........................................................14 3.1. Preparation of lactols from α-amino acids..........................14 3.2. Preparation of trans-oxazolidine derivatives......................15 3.3. Synthesis of bestatin derivatives and lapstatin derivatives....................18 4. Conclusion...........................................................................22 Experimental Details..................................................................24 APPENDICES..............................................................................34 1. List of 1H NMR Spectra of Selected Compounds...............34 2. List of 13C NMR Spectra of Selected Compounds..............52 REFERENCES.............................................................................70 ABSTRACT IN KOREAN............................................................72Maste

선진교통안전 의식 제고 방안

노트 : 본 간행물은 국토연구원에서 2014년 7월에 발행한 [안전한 국토와 국민행복 실현] 특집의 제 6부입니다

인간 혈관 세포에서 리지스틴이 CAP1-Adenylyl Cyclase-Caveolin Complex를 해체하여 면역 세포 부착 분자를 조절하는 기전에 관한 연구

학위논문 (석사)-- 서울대학교 융합과학기술대학원 : 분자의학 및 바이오제약학과, 2015. 2. 김효수.Resistin has been anticipated as a promising biomarker that could integrate metabolic disease and inflammatory disease. Resistin, first discovered as an adipokine, is often increased in patients with obesity and -inflammation. Due to increased level of resistin often corresponds to symptoms like insulin resistance and atherosclerosis, it is expected to be a linker that bridges the gap between metabolic disease and inflammation. However, there has been a controversy on whether resistin directly triggers insulin resistance or vascular inflammation, and the certainty of its receptor. Especially the uncertainty of receptor has been a considerable obstacle to research a causal relation of resistin to insulin resistance or atherosclerosis, and lastly developing a resistin-targeted drug. In this regard, our recent observation that adenylyl cyclase associated protein1 (CAP1) functioned as receptor of human resistin, shed light on molecular mechanisms of resistin action. Here, we showed that CAP1 is also a functional receptor of human resistin in endothelial cells with the mechanism being distinguished from monocytes due to particularly caveolae-enriched environments. In monocytes, the predominant adenylyl cyclase isoform localized on normal plasma membrane and resistin directly activated adenylyl cyclase through CAP1. Perplexingly in endothelial cells, the predominant isoform localized on caveolae and resistin indirectly de-suppressed adenylyl cyclase by disassembling CAP1-adenylyl cyclase-caveolin complex. Indeed CAP1 made an assembly with caveolin and adenylyl cyclase at normal state in human endothelial cells and the assembly was disorganized upon resistin treatment, leading to activation of cAMP-PKA-CREB signaling and NF-κB signaling pathway followed by overexpression of inflammatory adhesion molecules such as ICAM-1 and VCAM-1. Finally, we demonstrated these increased ICAM-1 and VCAM-1 effectively stimulated trans-endothelial migration of monocytes. Our findings revealed the new molecular mechanism on how resistin interacts with CAP1 and activates adenylyl cyclase in endothelial cells and consequently contributes to leukocyte infiltration.Abstract ⅰ Contents ⅳ List of Tables ⅴ List of Figures ⅵ List of Abbreviations ⅶ Introduction 1 Materials and Methods 7 Results 14 Discussion 26 Figures 32 References 53 Abstract (Korean) 64Maste

도로공사장 교통관리 실천방안 연구(A study of traffic management strategies for the road work zone in Seoul)

노트 : 이 보고서의 내용은 연구진의 견해로서 서울특별시의 정책과는 다를 수도 있습니다