Design, synthesis, and biological evaluation of iminosugars as pharmacological chaperone for Gaucher disease
Project/Area Number |
23590127
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Drug development chemistry
|
Research Institution | University of Toyama |
Principal Investigator |
KATO Atsushi 富山大学, 大学病院, 准教授 (60303236)
|
Co-Investigator(Kenkyū-buntansha) |
TAKAHATA Hiroki 東北薬科大学, 薬学部, 教授 (00109109)
HIRONO Shuichi 北里大学, 薬学部, 教授 (30146328)
ISHII Satoshi 大分大学, 医学部, 客員研究員 (00222935)
ADACHI Isao 富山大学, 大学病院, 教授 (30151070)
|
Project Period (FY) |
2011 – 2013
|
Project Status |
Completed (Fiscal Year 2013)
|
Budget Amount *help |
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
|
Keywords | リソソーム病 / グリコシダーゼ / イミノ糖 / シャペロン / フォールディング |
Research Abstract |
We report on the identification of the required configuration and binding orientation of iminosugars against b-glucocerebrosidase. A molecular docking study revealed that strong-binding iminosugars had a favorable van der Waals interactions and the hydrogen bonding. Calystegines, which is one of the candidates for pharmacological chaperone, bound into the same active site as isofagomine and the essential hydrogen bonds formed to Asp127, Glu235 and Glu340 were maintained. However, their binding orientations were obviously different. It is noteworthy that Type 1 orientated calystegines effectively stabilized b-glucocerebrosidase, and consequently increased intracellular b-glucocerebrosidase activities in N370S fibroblasts, while Type 2 orientated calystegines could not keep the enzyme activity. These results clearly indicate that the binding orientations of iminosugars are changed by the configuration of the hydroxyl groups.
|
Report
(4 results)
Research Products
(50 results)
-
[Journal Article] Docking and SAR studies of calystegines : binding orientation and influence on pharmacological chaperone effects for Gaucher’s disease.2014
Author(s)
Kato, A., Nakagome, I., Nakagawa, S., Koike, Y., Nash, R. J., Adachi, I., Hirono, S.
-
Journal Title
Bioorg. Med. Chem.
Volume: 22 (8)
Issue: 8
Pages: 2435-2441
DOI
Related Report
Peer Reviewed
-
[Journal Article] Synthesis of eight stereoisomers of pochonicine: Nanomolar inhibition of β-N-acetylhexosaminidases.2013
Author(s)
Zhu, J. -S., Nakagawa, S., Chen, W., Adachi, I., Jia, Y. -M., Hu, X. -G., Fleet, G. W. J., Wilson, F. X., Nitoda, T., Horne, G., van Well, R., Kato, A., Yu, C. -Y.
-
Journal Title
J. Org. Chem.
Volume: 78 (20)
Issue: 20
Pages: 10298-10309
DOI
Related Report
Peer Reviewed
-
[Journal Article] C-Branched iminosugars: α-glucosidase inhibition by enantiomers of isoDMDP, isoDGDP and isoDAB – L-isoDMDP compared to miglitol and miglustat.2013
Author(s)
Jenkinson, S. F., Best, D., Saville, A. W., Mui, J., Martinez, R. F., Nakagawa, S., Kunimatsu, T., Alonzi, D. S., Butters, T. D., Norez, C., Becq, F., Blériot, Y. Wilson, F. X., Weymouth-Wilson, A. C., Kato, A., Fleet, G. W. J.
-
Journal Title
J. Org. Chem.
Volume: 78 (15)
Issue: 15
Pages: 7373-7776
DOI
Related Report
Peer Reviewed
-
[Journal Article] (3R,4S,5R,6R,7S)-3,4,5,7-Tetrahydroxyconidine, anazetidine analogue of 6,7-diepicastanospermine and aconformationally constrained D-deoxyaltronojirimycin, from L-arabinose.2013
Author(s)
Martinez, R. F., Araujo, N., Jenkinson, S. F., Nakagawa, S., Kato, A., Fleet, G. W. J.
-
Journal Title
Bioorg. Med. Chem.
Volume: 21 (16)
Issue: 16
Pages: 4813-4819
DOI
Related Report
Peer Reviewed
-
[Journal Article] General synthesis of sugar-derived azepane nitrones: precursors of azepane iminosugars.2013
Author(s)
Zhao, W. -B., Nakagawa, S., Kato, A., Adachi, I., Jia, Y. -M., Hu, X. -G., Fleet, G. W. J., Wilson, F. X., Horne, G., Yoshihara, A., Izumori, K., Yu, C. -Y.
-
Journal Title
J. Org. Chem.
Volume: 78 (7)
Issue: 7
Pages: 3208-3221
DOI
Related Report
Peer Reviewed
-
[Journal Article] 3-Hydroxyazetidine carboxylic acids: non-proteinogenic amino acids for medicinal chemists.2012
Author(s)
Jenkinson, S. F., Thompson, A. L., Nakagawa, S., Kato, A., Butters, T. D., Fleet, G. W. J.
-
Journal Title
ChemMedChem.
Volume: 8 (4)
Issue: 4
Pages: 658-666
DOI
Related Report
Peer Reviewed
-
[Journal Article] α-1-C-Butyl-LAB as a second-generation iminosugar-based oral α-glucosidase inhibitor for improving postprandial hyperglycemia.2012
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.
-
Journal Title
J. Med. Chem.
Volume: 55 (23)
Issue: 23
Pages: 10347-10362
DOI
Related Report
Peer Reviewed
-
[Journal Article] Glycosidase inhibition by all 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols prepared from the enantiomers of glucuronolactone.2012
Author(s)
Ayers, B., Ngo, M., Jenkinson, S. F Martínez, R. F., Shimada, Y., Adachi, I., Weymouth-Wilson, A. C., Kato, A., Fleet, G. W. J.
-
Journal Title
J. Org. Chem.
Volume: 77 (18)
Issue: 18
Pages: 7777-7792
DOI
Related Report
Peer Reviewed
-
[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-mannitol.2012
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.
-
Journal Title
Org. Lett.
Volume: 14 (16)
Issue: 16
Pages: 4174-4177
DOI
Related Report
Peer Reviewed
-
[Journal Article] Scalable syntheses of both enantiomers of DNJNAc and DGJNAc from glucuronolactone: The effect of N-alkylation on hexosaminidase inhinition.2012
Author(s)
Glawar, A. Best, D., Ayers, B., Miyauchi, S., Nakagawa, S., Agulilar-M, M., Fernandez, J. M. G., Mellet, C. O., Crabtree, E. V., Butters, T. D., Wilson, F. X., Kato, A., Fleet, G. W. J.
-
Journal Title
Chem. Eur. J.
Volume: 18 (30)
Issue: 30
Pages: 9341-9359
DOI
Related Report
Peer Reviewed
-
[Journal Article] Azetidine iminosugars from the cyclization of 3,5-di-O-triflates of α-furanosides and of 2,4-O-triflates of β-pyranosides derived from glucose.2012
Author(s)
Lenagh-Snow, G. M. J., Araujo, N., Jenkinson, S. F., Martinez, R. F., Shimada, Y, Yu, C.-Y., Kato, A., Fleet, G. W. J.
-
Journal Title
Org. Lett.
Volume: 14 (8)
Issue: 8
Pages: 2142-2145
DOI
Related Report
Peer Reviewed
-
[Journal Article] Eight stereoisomers of homonojirimycin from D-mannose.2012
Author(s)
Lenagh-Snow, G. M. J., Jenkinson, S. F., Newberry, S. J., Kato, A., Nakagawa, S., Adachi, I., Wormald, M. R., Yoshihara, A., Morimoto, K., Akimitsu, K., Izumori, K., Fleet, G. W. J.
-
Journal Title
Org. Lett.
Volume: 14 (8)
Issue: 8
Pages: 2050-2053
DOI
Related Report
Peer Reviewed
-
[Journal Article] Inhibition of non-mammalian glycosidases by azetidine iminosugars derived from stable 3,5-di-O-triflates of pentoses2011
Author(s)
Lenagh-Snow, G. M. J., Araujo, N., Jenkinson, S. F., Rutherford, C., Nakagawa, S., Kato, A., Yu, C.-Y., Weymouth-Wilson, A. C., Fleet, G. W. J
-
Journal Title
Org. Lett
Volume: 13 (21)
Issue: 21
Pages: 5834-5837
DOI
Related Report
Peer Reviewed
-
[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
-
Journal Title
Org. Lett
Volume: 13 (15)
Issue: 15
Pages: 4064-4067
DOI
Related Report
Peer Reviewed
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
[Presentation] Synthesis amd biological evaluation of azetidines derivatives from carbohydrates2012
Author(s)
Araújo, N., Martínez, R. F., Lenagh-Snow, G. M. J., Glawar, A. F. G., Jenkinson, S. F., Kato, A., Fleet, G.W.J
Organizer
26^<th> International Carbohydrate Symposium (ICS2012)
Place of Presentation
Tokyo, Japan
Related Report
-
[Presentation] Synthesis of glycosidase inhibitors based on bicyclic azetidines for the treatment of cancer2012
Author(s)
Martínez, R. F., Araújo, N., Jenkinson, S. F., Kato, A., and Fleet, G. W. J
Organizer
26^<th> International Carbohydrate Symposium (ICS2012)
Place of Presentation
Tokyo, Japan
Related Report
-
-
-
-
[Presentation] Docking and SAR studies of D- and L-isofagomine isomers as humanβ-glucocerebrosidase inhibitors2012
Author(s)
Kato, A., Miyauchi, S., Nakagome, I., Yoshimura, Y., Hirono, S., Takahata, H., Adachi, I
Organizer
8th AFMC International Medicinal Chemistry Symposium (AIMECS11)
Place of Presentation
Keio, Japan
Related Report
-
[Presentation] Synthesis of glycosidase inhibitors based on bicyclic azetidines for the treatment of cancer.2012
Author(s)
Martinez, R. F., Araujo, N., Jenkinson, S. F., Kato, A., and Fleet, G. W. J
Organizer
26th International Carbohydrate Symposium (ICS2012)
Place of Presentation
Tokyo, Japan
Related Report
-
[Presentation] Synthesis and biological evaluation of azetidines derivatives from carbohydrates.2012
Author(s)
Araujo, N., Martinez, R. F., Lenagh-Snow, G. M. J., Glawar, A. F. G., Jenkinson, S. F., Kato, A., Fleet, G.W.J.
Organizer
26th International Carbohydrate Symposium (ICS2012)
Place of Presentation
Tokyo, Japan
Related Report
-
-
-
[Presentation] Docking and SAR studies of D- and L-isofagomine isomers as human β-glucocerebrosidase inhibitors2011
Author(s)
Kato, A., Miyauchi, S., Nakagome, I., Yoshimura, Y., Hirono, S., Takahata, H., Adachi, I.
Organizer
8th AFMC International Medicinal Chemistry Symposium (AIMECS11)
Place of Presentation
東京
Related Report