title: Isolation and SAR studies of bicyclic iminosugars from Castanospermum australe as glycosidase inhibitors.
abstract: 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.
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan. Electronic address: kato@med.u-toyama.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hirokami
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kinami
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Tsuji
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Miyawaki
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
authors.affiliation: Institute of Biological, Environmental and Rural Sciences/Phytoquest Limited, Plas Gogerddan, Aberystwyth, Ceredigion SY23 3EB, United Kingdom.
authors.forename: Jackie
authors.initials: J
authors.lastname: Hollinshead
authors.affiliation: Institute of Biological, Environmental and Rural Sciences/Phytoquest Limited, Plas Gogerddan, Aberystwyth, Ceredigion SY23 3EB, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nash
authors.affiliation: Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: J L
authors.initials: JL
authors.lastname: Kiappes
authors.affiliation: Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: Nicole
authors.initials: N
authors.lastname: Zitzmann
authors.affiliation: Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, MI 48202, United States.
authors.forename: Jin K
authors.initials: JK
authors.lastname: Cha
authors.affiliation: Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 34 Rainbow Drive, Hilo, HI 96720, United States.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Molyneux
authors.affiliation: Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom. Electronic address: george.fleet@chem.ox.ac.uk.
authors.forename: George W J
authors.initials: GW
authors.lastname: Fleet
authors.affiliation: BioApply Co., Ltd., 1-95 Tsuchishimizu, Kanazawa 920-0955, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Asano
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D031291:Castanospermum / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D005944:Glucosamine / Q000031:analogs & derivatives / Q000737:chemistry; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D050111:Imino Sugars / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D007212:Indolizines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D054836:Indolizidines
chemical_list: D017485:1-Deoxynojirimycin; D000470:Alkaloids; D004791:Enzyme Inhibitors; D005944:Glucosamine; D006026:Glycoside Hydrolases; D007004:Hypoglycemic Agents; D050111:Imino Sugars; D007212:Indolizines; D010880:Piperidines; C478924:1-deoxy-nojirimycin; C045621:miglitol; C037806:castanospermine; D054836:Indolizidines
keywords: Australine; Castanospermine; Castanospermum australe; Glycosidase inhibitor; Iminosugar; Structure–activity relationship