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Kato A.,University of Toyama | Miyauchi S.,University of Toyama | Kato N.,University of Toyama | Nash R.J.,Environmental and Rural science Phytoquest Ltd | And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011

We report the structure-activity relationship of a series of d-, and l-isofagomine and fagomine isomers as glycosidase inhibitors. Our study revealed that a positive charge at the anomeric position of d-isofagomines enhanced the potency toward β-glycosidases, while the epimerization at the C3 OH group drastically reduced their inhibitory potency by over three orders of magnitude. Furthermore, d-3,4-di-epi-isofagomine abolished their inhibition activities against all enzymes. l-Isofagomine was also a fairly potent inhibitor of human β-glucocerebrosidase, with an IC 50 value of 8.7 μM. A molecular docking study revealed that the positions and orientations of the piperidine ring of d-3-epi-isofagomine in the binding site was similar to that of d-isofagomine, while d-3-epi-isofagomine missed the hydrogen bond interactions between Asp127 and the 3-OH group and between Trp179 and the 3-OH group. Furthermore, the top 10 docking models ranked by IFDscore suggested that d-3,4-di-epi-isofagomine can not bind to β-glucocerebrosidase at a stable interaction mode. These results provide an insight into the structural requirements of isofagomine isomers for developing a new type of pharmacological chaperone for Gaucher disease. © 2011 Elsevier Ltd. All rights reserved. Source


Kato A.,University of Toyama | Hollinshead J.,Environmental and Rural science Phytoquest Ltd | Yamashita Y.,University of Toyama | Nakagawa S.,University of Toyama | And 5 more authors.
Phytochemistry Letters | Year: 2010

The distribution of pyrrolidine-type iminosugars with a long-side chain appears to be restricted to the relatively unrelated plant families Moraceae, Campanulaceae, and Hyacinthaceae. In a search for glycosidase inhibitors in these plant families, we isolated the 1,4-dideoxy-1,4-imino-d-lyxitol (DIL) glucoside bearing the 1,2,11-trihydroxyundec-4-ene side chain at the C-1α position from the roots of Adenophora triphylla. This iminosugar was a powerful and selective inhibitor of coffee bean α-galactosidase, with an IC 50 value of 8 μM. © 2010 Phytochemical Society of Europe. Source


Kato A.,University of Toyama | Yamashita Y.,University of Toyama | Nakagawa S.,University of Toyama | Koike Y.,University of Toyama | And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

Chromatographic separation of the extract from roots of Adenophora triphylla resulted in the isolation of two pyrrolidines, six piperidines, and two piperidine glycosides. The structures of new iminosugars were elucidated by spectroscopic methods as 2,5-dideoxy-2,5-imino-d-altritol (DIA) (2), β-1-C-butenyl-1-deoxygalactonojirimycin (8), 2,3-dideoxy-β-1-C-ethyl-1-deoxygalactonojirimycin (9), and 6-O-β-d-glucopyranosyl-2,3-dideoxy-β-1-C-ethyl-1-deoxygalactonojirimycin (10). β-1-C-Butyl-1-deoxygalactonojirimycin (7) and compound 8 were found to be better inhibitors of α-galactosidase than N-butyl-1-deoxygalactonojirimycin. The present work elucidated that DIA was a powerful competitive inhibitor of human lysosome α-galactosidase A (α-Gal A) with a Ki value of 0.5 μM. Furthermore, DIA improved the thermostability of α-Gal A in vitro and increased intracellular α-Gal A activity by 9.6-fold in Fabry R301Q lymphoblasts after incubation for 3 days. These experimental results suggested that DIA would act as a specific pharmacological chaperone to promote the smooth escape from the endoplasmic reticulum (ER) quality control system and to accelerate transport and maturation of the mutant enzyme. © 2010 Elsevier Ltd. All rights reserved. Source


Kato A.,University of Toyama | Hirokami Y.,University of Toyama | Kinami K.,University of Toyama | Tsuji Y.,University of Toyama | And 10 more authors.
Phytochemistry | Year: 2015

We report the isolation and structural determination of fourteen iminosugars, containing five pyrrolizidines and five indolizidines, from Castanospermum australe. The structure of a new alkaloid was elucidated by spectroscopic methods as 6,8-diepi-castanospermine (13). Our side-by-side comparison between bicyclic and corresponding monocyclic iminosugars revealed that inhibition potency and spectrum against each enzyme are clearly changed by their core structures. Castanospermine (10) and 1-deoxynojirimycin (DNJ) have a common d-gluco configuration, and they showed the expected similar inhibition potency and spectrum. In sharp contrast, 6-epi-castanospermine (12) and 1-deoxymannojirimycin (manno-DNJ) both have the d-manno configuration but the α-mannosidase inhibition of 6-epi-castanospermine (12) was much better than that of manno-DNJ. 6,8-Diepi-castanospermine (13) could be regarded as a bicyclic derivative of talo-DNJ, but it showed a complete loss of α-galactosidase A inhibition. This behavior against α-galactosidase A is similar to that observed for 1-epi-australine (6) and altro-DMDP. © 2014 Elsevier Ltd. All rights reserved. Source

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