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사이클리톨 유도체인 UDP-carba-GlcNAc, a-GalCer의 carbasugar 유사체, 그리고 myo-IP1과 IP2의 합성 및 응용연구

Title
사이클리톨 유도체인 UDP-carba-GlcNAc, a-GalCer의 carbasugar 유사체, 그리고 myo-IP1과 IP2의 합성 및 응용연구
Authors
서경창
Date Issued
2010
Publisher
포항공과대학교
Abstract
Part 1. Synthetic and Biological Studies of UDP-carba-GlcNAc. O-GlcNAc transferase (OGT) is a class of enzymes that transfer the GlcNAc moiety from UDP-GlcNAc to serine and threonine residues of some important nuclear and cytoplasmic proteins. For the purpose of providing a metabolically stable inhibitor for OGT, UDP-carba-GlcNAc 1, where the ring oxygen of the GlcNAc residue is replaced by a methylene group was chemoenzymatically prepared. From a carba-b-GlcNAc derivative 13, the a-stereoisomer 14 was obtained via mesylation followed by nucleophilic substitution with CsOAc. The carba-a-GlcNAc derivative was then enzymatically converted to UDP-carba-GlcNAc 1 via a phosphorylated derivative 18. In vitro, the title compound showed an weak inhibitory activity with a IC50 value of 430mM toward ncOGT by using casein kinase (CKII), known to be a good OGT substrate. This weak inhibitory activity of UDP-carba-GlcNAc 1 may result from too high a rigid binding site structure of the OGT active site. In addition, chemoenzymatic syntheses of several other NDP-cabar-sugars including UDP-carba-Gal 19, UDP-carba-Glc 20, and GDP-carba-Man 21 have also been successfully carried out, and these essential cofactor analogues are expected to be selective inhibitors of various glycosyltransferase enzymes.
Part 2. Synthetic and Biological Studies of Carbasugar-based KRN7000 Analogues. KRN7000 (a-GalCer) is an important bridging ligand for CD1d protein of APC, and the KRN7000/CD1d complex can stimulate NKT cells to release a broad range of bioactive cytokines. A number of KRN7000 analogues have been prepared and their biological properties evaluated in order to shed some light on the binding interaction between a-GalCer and CD1d, and also to selectively control the cytokine release profile by NKT cells toward either Th1 or Th2. From our syntheses of a complete set of the eight KRN7000 stereoisomers and a series of compounds in which various combinations of the aromatic residue in both N-acyl and backbone chains and the backbone stereochemistry had been made, we selected some interesting compounds and synthesized their carbasugar-based analogues (1 ~ 7), which were expected to have better cytokine release properties because of their metabolical stability. Carba-a-galactose derivative 32 was coupled with cyclic sulfamidates (33 ~ 38). Deprotection of all benzyl groups, followed by selective acylation gave the desired carbasugar-based KRN7000 analgoues. In vitro assay, at least two of carbasugar variants appeared more active than KRN7000, particularly with regard to IFN-g production. In vivo, compound 1, which has the exactly same ceramide structure as KRN7000 except the carbasugar residue, biased toward Th1. Compound 2 has double bonds-inserted acyl chain and showed Th2-biased cytokine response, consistent with the corresponding O-sugar compound. Compounds 3 and 4 have an aromatic residue each in the phytosphingosine chain, and they also show Th2-biased activity. Compound 7 which has a simple amino alcohol skeleton did not show any uniquely interesting activity.
Part 3. Synthetic Studies of Optically Active Inositol mono- and bis-phosphates and Their Biochemical Applications. We previously reported the systematic and divergent syntheses of all possible 39 optically inactive regioisomers of myo-inositol phosphates using the acyl migration as the key strategy and also 32 optically active regioisomers of myo-inositol tris-, tetrakis- and pentakis-phosphates using the Candida rugosa lipase (CRL)-catalyzed enzymatic resolution and the acyl migration. All possible optically active regioisomers of myo-inositol mono- (1) and bis-phosphates (2) had been synthesized using inositol derivatives suitably protected with various protecting groups (IRns) as key intermediates. A series of procedures including several protection and deprotection reactions, and acyl migrations afforded two enantiomeric pairs of IR5 (7, 13) and six enantiomeric pairs of IR4 (5, 8, 11, 14, 16, 17), respectively. Phosphorylation of these key intermediates by the phosphitylation and oxidation procedure gave the target products, after removal of the protecting groups, thus now completing the syntheses of all possible 63 (15 meso and 24 enantiomeric pairs) regioisomers of myo-inositol phosphates. Using these IP analogues had allowed the first biochemical study comparing two identifed IMPases gene products, the well characterized IMPA1 and IMPA2. IMPase, which is the target of lithium ion in the treatment of manic depression and its accompanying CNS toxicity, is an important research topic in molecular psychiatry. IMPA2 has intrinsic IMPase activity that is completely dependent on magnesium, albeit this activity is much weaker than that of IMPA1 in assay conditions. And IMPA2 was bound to have an optimal pH and magnesium concentration distinct to that of IMPA1, and its IMPases activity was much less sensitive to lithium than that of IMPA1, when I(1)P1 was used as a substrate.
URI
http://postech.dcollection.net/jsp/common/DcLoOrgPer.jsp?sItemId=000000538656
http://oasis.postech.ac.kr/handle/2014.oak/506
Article Type
Thesis
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