2012 Fiscal Year Final Research Report
Inhibition activities of iminosugars against glycoprotein processing
| Project/Area Number |
22590059
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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 |
Biological pharmacy
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| Research Institution | University of Toyama |
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Principal Investigator |
ADACHI Isao 富山大学, 大学病院, 教授 (30151070)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHATA Hiroki 東北薬科大学, 薬学部, 教授 (00109109)
KATO Atsushi 富山大学, 大学病院, 准教授 (60303236)
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| Project Period (FY) |
2010 – 2012
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| Keywords | イミノ糖 / グリコシダーゼ / 光学異性体 / リソソーム病 / シャペロン |
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| Research Abstract |
We studied the concise synthesis of DGJ and L-DGJ from L- and D-tagatose respectively in just four steps, and shows the value of the enantiomers of tagatose as chirons. As with other α-galactosidases L-DGJ was found to be an inhibitor of α-Gal A, about 1000-fold weaker than its enantiomer DGJ. L-DGJ was also found to be a chaperone for α-Gal A, again about 1000 times less active than DGJ. Non-competitive inhibition by L-DGJ is consistent with binding at a different site than DGJ which shows competitive inhibition and binds at the active site. While the inhibition of the same glycosidase by both enantiomers of an iminosugar is well-known, this is the first example of enantiomeric iminosugars acting as synergistic pharmacological chaperones for misfolded proteins; this result may indicate that binding at the active site of the enzyme is not necessary. There are many hundreds of pyrrolidine, piperidine and azepane sugar mimics but azetidines are only just beginning to be studied. There are few examples of carbohydratederived azetidines, although the properties of hydroxyazetidines are of current interest. N-Alkyl hydroxyazetidines are potent inhibitors of purine nucleoside phosphorylase with subnanomolar Ki. We studied the synthesis of an azetidine analogue of 6,7-diepicastanospermine and compares its glycosidase activity also with D-altronojirimycin.
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Research Products
(17 results)
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[Journal Article] α-1-C-Butyl-LAB as a second-generation iminosugar-based oral α-glucosidase inhibitor for improving postprandial hyperglycemia2012
Author(s)
Kato, A., Hayashi, E., Miyauchi, S., Adachi, I., Imahori, T., Natori, Y., Yoshimura, Y., Nash, R. J., Shimaoka, H., Nakagome, I., Koseki, J., Hirono, S., Takahata, H
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Journal Title
J. Med. Chem
Volume: 55(23)
Pages: 10347-10362
Peer Reviewed
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[Journal Article] Synthesis from D-altrose of (5R,6R,7R,8S)-5,7-dihydroxy-8-hydroxymethylconidine and 2,4-dideoxy-2,4-imino-D-glucitol, azetidine analogues of swainsonine and 1,4-dideoxy-1,4-imino-D-mannitol2012
Author(s)
Araujo, N., Jenkinson, S. F., Martinez, R. F., Glawar, A. F. G., Wormald, M. R., Butters, T. D., Nakagawa, S., Adachi, I., Kato, A.Yoshihara, A., Akimitsu, K., Izumori, K., Fleet, G. W. J
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Journal Title
Org. Lett
Volume: 14(16)
Pages: 4174-4177
Peer Reviewed
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[Journal Article] Asymmetric synthesis of 1-alkyl-2-deoxyiminofuranoses via The iridium-catalyzed intramolecular cyclization of an allylic carbonate2012
Author(s)
Natori, Y., Kikuchi, S., Yoshimura, Y., Kato, A., Adachi, I., Takahata, H
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Journal Title
Heterocycles
Volume: 86(2)
Pages: 1401-1417
Peer Reviewed
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[Journal Article] Asymmetric synthesis of 2-propylisofagomine using allylic hydroxy group accelerated ring-closing enyne metathesis2012
Author(s)
Taguchi, T., Imahori, T., Yoshimura, Y., Kato, A., Adachi, I., Kawahara, M., Yamaguchi, K., Takahata, H
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Journal Title
Heterocycles
Volume: 84(2)
Pages: 929-944
Peer Reviewed
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[Journal Article] Synthesis, conformational analysis, and evaluation as glycosidase inhibitors of two ether-bridged iminosugars2011
Author(s)
Luo, B., Marcelo, F., Desire, J., Zhang, Y., Sollogoub, M., Kato, A., Adachi, I., Canada, F. Jimenez-Barbero, J., Bleriot, Y
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Journal Title
J. Carb. Chem
Volume: 30(7-9)
Pages: 641-654
Peer Reviewed
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[Journal Article] Looking-glass synergistic pharmacological chaperones: DGJ and L-DGJ from the enantiomers of tagatose2011
Author(s)
Jenkinson, S. F., Fleet, G. W. J., Nash, R. J., Koike, Y., Adachi, I., Yoshihara, A., Morimoto, K., Izumori, K., Kato, A
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Journal Title
Org. Lett
Volume: 13(15)
Pages: 4064-4067
Peer Reviewed
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