2006 Fiscal Year Final Research Report Summary
Design and synthesis of sugar nucleotide analogues as the inhibitors against glycosyltransferases
| Project/Area Number |
17590024
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Kyoto Pharmaceutical University |
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Principal Investigator |
KAJIMOTO TETSUYA Kyoto Pharmaceutical University, Department of Pharmaceutical Sciences, Associate Prof., 薬学部, 助教授 (80185777)
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| Co-Investigator(Kenkyū-buntansha) |
TSUJI SHUICHI Tokai University, Institute of Future Science and Technology, Professor, 未来科学技術共同センター, 教授 (90124677)
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| Project Period (FY) |
2005 – 2006
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| Keywords | glycosyltransferase / inhibitor / sugar nucleotide analogues / nikkomycin / polyoxin / acceptor treisaccharide / enzymatic aldol reaction / L-threonine aldolase |
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| Research Abstract |
Inhibitors against glycosyltransferases and glycosidases, which build up oligosaccharide moieties of biologically active glycoconjugates, are essential tools for the development of glycobiology and promising candidates of novel agents for the treatments of tumors, inflammatory, autoimmune diseases, and bacterial and virus infections. Many excellent inhibitors against glycosidases, such as deoxynojirimycin and oseltamivir, were found from nature and developed by good combination of structural biology and synthetic chemistry. However, excellent inhibitors of glycosyltransferases have not been developed until recently, because of little information on the structures of active sites of the enzymes, involvement of several components in the transition state of the enzyme catalyzed reaction, low affinities between the enzymes and substrates, and no facile assay systems for the inhibitory activities. Therefore, we embarked on design and synthesis of sugar nucleotide analogues as the inhibitors against glycosyltransferases since the sugar nulcleotides are donor substrates of the enzymes. Fortunately, nikkomycin and polyoxins, peptidic analogues of sugar nucleotide are already used practically for the treatment of some skin diseases caused by Candida sp. and as agrochemicals. Thus, we started these compounds by using L-threonine aldolase-catalyzed enzymatic aldol reaction, which afford fl-hydroxy-cc-L-amino acids under completely physiological conditions. Finally, we succeeded in the formal total synthesis of polyoxin C in good overall yield in the shortest step within those reported so far. In addition, a trisaccharide which could be an acceptor substrate of N-acetylglucosaminyltransferase V was faciley synthesized by using thioglycosyl donor, which was prepared by using novel odorless benzenethiols.
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Research Products
(11 results)
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[Journal Article] Fluorescence modification of Gb3 oligosaccharide and rapid synthesis of oligosaccharide moieties using fluorous protective group2005
Author(s)
T.Miura, S.Tsujino, A.Satoh, K.Goto, M.Mizuno, M.Noguchi, T.Kajimoto, M.Node, Y.Murakami, N.Imai, T.Inazu
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Journal Title
Tetrahedron 61
Pages: 6518-6526
Description
「研究成果報告書概要(欧文)」より
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