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1.
Amino Acids ; 51(7): 991-998, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31079215

ABSTRACT

DMDP acetic acid [N-carboxymethyl-2,5-dideoxy-2,5-imino-D-mannitol] 5 from Stevia rebaudiana is the first isolated natural amino acid derived from iminosugars bearing an N-alkyl acid side chain; it is clear from GCMS studies that such derivatives with acetic and propionic acids are common in a broad range of plants including mulberry, Baphia, and English bluebells, but that they are very difficult to purify. Reaction of unprotected pyrrolidine iminosugars with aqueous glyoxal gives the corresponding N-acetic acids in very high yield; Michael addition of both pyrrolidine and piperidine iminosugars and that of polyhydroxylated prolines to tert-butyl acrylate give the corresponding N-propionic acids in which the amino group of ß-alanine is incorporated into the heterocyclic ring. These easy syntheses allow the identification of this new class of amino acid in plant extracts and provide pure samples for biological evaluation. DMDP N-acetic and propionic acids are potent α-galactosidase inhibitors in contrast to potent ß-galactosidase inhibition by DMDP.


Subject(s)
Acetates/chemical synthesis , Amino Acids/chemistry , Glycoside Hydrolases/antagonists & inhibitors , Imino Sugars/isolation & purification , Propionates/chemical synthesis , Pyrrolidines/chemical synthesis , Stevia/chemistry , Amino Acids/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Gas Chromatography-Mass Spectrometry , Glycine/chemistry , Glycosides/metabolism , Hydroxyproline/chemistry , Imino Sugars/chemistry , Piperidines/chemical synthesis , alpha-Galactosidase/antagonists & inhibitors , beta-Alanine/chemistry , beta-Galactosidase/antagonists & inhibitors
2.
Phytochemistry ; 111: 124-31, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25583438

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.


Subject(s)
Alkaloids/isolation & purification , Alkaloids/pharmacology , Castanospermum/chemistry , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Imino Sugars/isolation & purification , Imino Sugars/pharmacology , Indolizines/isolation & purification , Indolizines/pharmacology , 1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Alkaloids/chemistry , Enzyme Inhibitors/chemistry , Glucosamine/analogs & derivatives , Glucosamine/chemistry , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Imino Sugars/chemistry , Indolizines/chemistry , Piperidines/pharmacology , Stereoisomerism , Structure-Activity Relationship
3.
Phytochemistry ; 109: 76-83, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25468536

ABSTRACT

Ten phenylalkyl-substituted iminosugars (1-10) and a cinnamic acid derived glucoside (11) were isolated from the roots of Glyphaea brevis (Malvaceae). Their structures were elucidated by 1D and 2D NMR analysis, as well as by HR-ESIMS. Compounds 1-10 retain an unprecedented structure composed of an iminosugar-like core identified as 1-deoxyfuconojirimycin in glyphaeaside A1-A4 (1, 2, 5, 6), 1-deoxygalactonojirimycin in glyphaeaside B1-B5 (3, 4, 7-9) or 1-deoxynojirimycin in glyphaeaside C (10), substituted by a ß-d-glucopyranose in compounds 2, 4, 6 and 9. These compounds feature a di-, tri- or tetra-hydroxylated nine-carbon chain at the pseudo-anomeric position, substituted by a terminal phenyl group. All alkyl C-iminosugars displayed potent and selective inhibition towards ß-glucosidase with IC50 values ranging from 0.15 to 68µM. Compound 10 with an 1-deoxynojirimycin backbone was the most active and was found to act as a competitive inhibitor with Ki=31nM, therefore emerging as one of the most potent inhibitor of ß-glucosidase reported to date. Inhibition of ß-mannosidase was observed with compounds 1, 3, 7 and 10, but only weak inhibition could be detected with the alkyl-C-iminosugars on the other tested glycosidases (α-glucosidase, α-fucosidase, α- and ß-galactosidase).


Subject(s)
Enzyme Inhibitors/chemistry , Glycoside Hydrolases/antagonists & inhibitors , Imino Sugars/chemistry , Malvaceae/chemistry , Plant Roots/chemistry , Enzyme Inhibitors/isolation & purification , Imino Sugars/isolation & purification , Inhibitory Concentration 50 , Molecular Structure
4.
Carbohydr Res ; 384: 9-12, 2014 Jan 30.
Article in English | MEDLINE | ID: mdl-24334235

ABSTRACT

Phytochemical investigation of the H2O extract of leaves of Suregada glomerulata led to the isolation of ten pyrrolidine-type iminosugars. The chemical structures of the six new compounds (4-6, 8-10) were elucidated as 2,5-imino-2,4,5-trideoxy-d-manno-heptitol (4-deoxy-homoDMDP) (4), 2,5-imino-2,4,5-trideoxy-d-gulo-heptitol (5), 2,5-imino-2,4,5,6-tetradeoxy-d-gulo-heptitol (6), 6-C-butyl-4-deoxy-DMDP (8), 6-C-(8-hydroxyoctyl)-DMDP (9), and 6-C-(8-hydroxyoctyl)-2,5-dideoxy-2,5-imino-d-galactitol (10), respectively, on the basis of spectroscopic data analysis (NMR and HRESIMS). Compounds 4-6 and 8 were characterized as rarely seen 4-deoxy pyrrolidine-type iminosugars. Pyrrolidine-type iminosugars with a long-side chain have been found in the restrictive plant families Moraceae, Campanulaceae, and Hyacinthaceae. The discovery of compounds 9 and 10 with a C8 side chain from S. glomerulata (Euphorbiaceae) expands the range of distribution for the iminosugars in plants. The 8-hydroxyoctyl side-chain represents a new addition for the molecular diversity of iminosugars. The compounds 1-10 were evaluated for inhibitory activity against rat intestinal α-glucosidase. However, all the test compounds showed no significant inhibitory activities to the glucosidase.


Subject(s)
Imino Sugars/chemistry , Imino Sugars/isolation & purification , Plant Leaves/chemistry , Pyrrolidines/chemistry , Suregada/chemistry , Molecular Conformation , Stereoisomerism
5.
Bioorg Med Chem ; 21(21): 6796-803, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-23993676

ABSTRACT

A water extract of the leaves of Suregada glomerulata (Euphorbiaceae) was found to inhibit rat small intestinal α-glucosidase. An examination of the extract afforded 20 iminosugars including one pyrrolidine and 19 piperidines. The structures of the 10 new compounds (11-20) were determined by NMR, and MS spectroscopic data analyses, and chemical correlations. The novelty of the identified compounds mainly stems from the loss of a hydroxy at C-4 and the presence of an 8-hydroxyoctyl side chain. Nine N-alkyl derivatives including N-methyl (1a, 8a, and 13a), N-butyl (1b, 2b, and 9b) and N,N-dimethyl (1c, 2c, and 9c) were synthesized. The compounds were tested for rat small intestinal α-glucosidase inhibitory activity. In total, 15 compounds, including compounds 11, 12, 15, and 19 and the three derivatives 8a, 9b, and 13a, showed inhibitory activity with IC50 values less than 40µM. In vivo results showed that total alkaloids of S. glomerulata (10mg/kg) and four major iminosugars 1, 2, 3, and 9 (10mg/kg) can lower the postprandial blood glucose level after sucrose and starch load in healthy male ICR mice.


Subject(s)
Enzyme Inhibitors/chemistry , Glycoside Hydrolase Inhibitors , Hypoglycemic Agents/chemistry , Imino Sugars/chemistry , Suregada/chemistry , Animals , Blood Glucose/analysis , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Hyperglycemia/drug therapy , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/therapeutic use , Imino Sugars/isolation & purification , Imino Sugars/metabolism , Intestine, Small/enzymology , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred ICR , Molecular Conformation , Plant Leaves/chemistry , Plant Leaves/metabolism , Protein Binding , Rats , Suregada/metabolism , alpha-Glucosidases/metabolism
6.
Bioorg Med Chem ; 18(11): 3790-4, 2010 Jun 01.
Article in English | MEDLINE | ID: mdl-20457528

ABSTRACT

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), beta-1-C-butenyl-1-deoxygalactonojirimycin (8), 2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (9), and 6-O-beta-d-glucopyranosyl-2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (10). beta-1-C-Butyl-1-deoxygalactonojirimycin (7) and compound 8 were found to be better inhibitors of alpha-galactosidase than N-butyl-1-deoxygalactonojirimycin. The present work elucidated that DIA was a powerful competitive inhibitor of human lysosome alpha-galactosidase A (alpha-Gal A) with a K(i) value of 0.5muM. Furthermore, DIA improved the thermostability of alpha-Gal A in vitro and increased intracellular alpha-Gal A activity by 9.6-fold in Fabry R301Q lymphoblasts after incubation for 3days. 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.


Subject(s)
Fabry Disease/drug therapy , Molecular Chaperones/chemistry , Phytotherapy/methods , Sugar Alcohols/therapeutic use , Campanulaceae/chemistry , Humans , Imino Sugars/isolation & purification , Mutant Proteins/metabolism , Piperidines/isolation & purification , Plant Extracts/chemistry , Protein Transport , Pyrrolidines/isolation & purification , Sugar Alcohols/isolation & purification , alpha-Galactosidase/antagonists & inhibitors
7.
Phytochemistry ; 69(5): 1261-5, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18191969

ABSTRACT

Chromatographic separation of the 50% aqueous EtOH extract of the leaves of the African medicinal tree Baphia nitida resulted in isolation of 10 iminosugars. The plant contained 2R,5R-dihydroxymethyl-3R,4R-dihydroxypyrrolidine (DMDP) as a major alkaloid. The structure of a new alkaloid was also elucidated by spectroscopic methods as the 1-O-beta-D-fructofuranoside of DMDP, and this plant produced 3-O-beta-D-glucopyranosyl-DMDP as well. DMDP is a potent inhibitor of beta-glucosidase and beta-galactosidase, whereas the other two derivatives lowered inhibition toward both of these enzymes and improved inhibitory activities toward rice alpha-glucosidase and rat intestinal maltase.


Subject(s)
Alkaloids/chemistry , Enzyme Inhibitors/chemistry , Fabaceae/chemistry , Imino Sugars/chemistry , Mannitol/analogs & derivatives , Plant Extracts/chemistry , Alkaloids/isolation & purification , Alkaloids/pharmacology , Animals , Candida/enzymology , Carbohydrate Conformation , Cattle , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors , Imino Furanoses/chemistry , Imino Furanoses/isolation & purification , Imino Furanoses/pharmacology , Imino Sugars/isolation & purification , Imino Sugars/pharmacology , Intestines/enzymology , Liver/enzymology , Mannitol/chemistry , Mannitol/isolation & purification , Mannitol/pharmacology , Oryza/enzymology , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Plant Leaves/chemistry , Rats , Stereoisomerism , Sucrase/antagonists & inhibitors , Swine , beta-Galactosidase/antagonists & inhibitors , beta-Glucosidase/antagonists & inhibitors
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