Isolation and SAR studies of bicyclic iminosugars from Castanospermum australe as glycosidase inhibitors

• Published in: Phytochemistry (Oxford) Vol. 111; pp. 124 - 131
• Main Authors: Kato, Atsushi, Hirokami, Yuki, Kinami, Kyoko, Tsuji, Yutaro, Miyawaki, Shota, Adachi, Isao, Hollinshead, Jackie, Nash, Robert J., Kiappes, J. L., Zitzmann, Nicole, Cha, Jin K., Molyneux, Russell J., Fleet, George W. J., Asano, Naoki
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 01.03.2015
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - chemistry; 1-Deoxynojirimycin - pharmacology; Alkaloids - chemistry; Alkaloids - isolation & purification; Alkaloids - pharmacology; Biochemistry & Molecular Biology; Castanospermum - chemistry; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Glucosamine - analogs & derivatives; Glucosamine - chemistry; Glycoside Hydrolases - antagonists & inhibitors; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Imino Sugars - chemistry; Imino Sugars - isolation & purification; Imino Sugars - pharmacology; Indolizines - chemistry; Indolizines - isolation & purification; Indolizines - pharmacology; Life Sciences & Biomedicine; Piperidines - pharmacology; Plant Sciences; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Australine; GLUCURONOLACTONE; Glycosidase inhibitor; Iminosugar; ENANTIOSELECTIVE SYNTHESIS; PYRROLIZIDINE ALKALOIDS; Castanospermine; ALPHA-GLUCOSIDASE; BIOLOGICAL-ACTIVITIES; GAUCHER-DISEASE; CHAPERONE ACTIVITY; Structure-activity relationship; CELGOSIVIR; Castanospermum australe; POLYHYDROXYLATED PYRROLIDINE; NATURAL OCCURRENCE; Structure–activity relationship
• ISSN: 0031-9422; 1873-3700
• DOI: 10.1016/j.phytochem.2014.12.011

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 alpha-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 alpha-galactosidase A inhibition. This behavior against alpha-galactosidase A is similar to that observed for 1-epi-australine (6) and altro-DMDP. (C) 2014 Elsevier Ltd. All rights reserved.