86 research outputs found
νΈλμ€-μ₯μ¬μ‘Έλ¦¬λ λ©νΈ μμ€ν° μ ν€μ μμ©μ ν΅ν κ°λ₯ν μλ―Έλ Έν©ν°λ€μμ μ΅μ μ λ€μ μ 체μ νμ μΈ ν©μ±
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Όλ¬Έ (μμ¬)-- μμΈλνκ΅ λνμ : ννμ물곡νλΆ, 2015. 8. κΉμκ·.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 Ξ²-amino-Ξ±-hydroxy acids were prepared via intramolecular conjugate addition between phenylsulfonylnitromethane and N-hydroxymethyl protected Ξ±-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 Ξ²-amino-Ξ±-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 Ξ²-amino-Ξ±-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-Ξ²-amino-Ξ±-hydroxy acid...........................................4
2. Background for the present study........................................8
2.1. N,O-Acetal lactols derived from Ξ±-amino acids....................8
2.2. Stereoselective synthesis of
threo-Ξ²-amino-Ξ±-hydroxy acids.........................................9
2.3. Synthetic plans for derivatives of
aminopeptidase inhibitors....................................................11
3. Results and Discussion........................................................14
3.1. Preparation of lactols from Ξ±-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
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μΈκ° νκ΄ μΈν¬μμ 리μ§μ€ν΄μ΄ CAP1-Adenylyl Cyclase-Caveolin Complexλ₯Ό ν΄μ²΄νμ¬ λ©΄μ μΈν¬ λΆμ°© λΆμλ₯Ό μ‘°μ νλ κΈ°μ μ κ΄ν μ°κ΅¬
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Όλ¬Έ (μμ¬)-- μμΈλνκ΅ μ΅ν©κ³ΌνκΈ°μ λνμ : λΆμμν λ° λ°μ΄μ€μ μ½νκ³Ό, 2015. 2. κΉν¨μ.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-ΞΊB 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 β
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Contents β
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List of Tables β
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List of Figures β
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List of Abbreviations β
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Introduction 1
Materials and Methods 7
Results 14
Discussion 26
Figures 32
References 53
Abstract (Korean) 64Maste
A Study on Creating Significance of Corporate Image Newspaper Advertisement - Centered on Models of Roland Barte and Jean Marie Floch -
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A Study on Public Communication Campaigns to Improve Recognition on Cardio-Cerebrovascular Disease
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