RESUMO
The enantiomers of XYLNAc (2-N-acetylamino-1,2,4-trideoxy-1,4-iminoxylitol) are prepared from the enantiomers of glucuronolactone; the synthesis of the enantiomers of LYXNAc (2-N-acetylamino-1,2,4-trideoxy-1,4-iminolyxitol) from an L-arabinono-δ-lactone and a D-ribono-δ-lactone is reported. A comparison is made of the inhibition of ß-N-acetylhexosaminidases (HexNAcases) and α-N-acetylgalactosaminidase (α-GalNAcase) by 8 stereoisomeric 2-N-acetylamino-1,2,4-trideoxy-1,4-iminopentitols; their N-benzyl derivatives are better inhibitors than the parent compounds. Both XYLNAc and LABNAc are potent inhibitors against HexNAcases. None of the compounds show any inhibition of α-GalNAcase.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Iminas/química , Iminas/farmacologia , Xilitol/análogos & derivados , Xilitol/síntese química , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Fabaceae/enzimologia , Pirrolidinas/química , Estereoisomerismo , Xilitol/química , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
All 16 stereoisomeric N-methyl 5-(hydroxymethyl)-3,4-dihydroxyproline amides have been synthesized from lactones accessible from the enantiomers of glucuronolactone. Nine stereoisomers, including all eight with a (3R)-hydroxyl configuration, are low to submicromolar inhibitors of ß-N-acetylhexosaminidases. A structural correlation between the proline amides is found with the ADMDP-acetamide analogues bearing an acetamidomethylpyrrolidine motif. The proline amides are generally more potent than their ADMDP-acetamide equivalents. ß-N-Acetylhexosaminidase inhibition by an azetidine ADMDP-acetamide analogue is compared to an azetidine carboxylic acid amide. None of the amides are good α-N-acetylgalactosaminidase inhibitors.
Assuntos
Acetamidas/química , Amidas/química , Ácido Azetidinocarboxílico/química , Prolina/análogos & derivados , Prolina/química , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Cinética , Estereoisomerismo , beta-N-Acetil-Hexosaminidases/químicaRESUMO
The scarcity and expense of access to L-sugars and other rare sugars have prevented the exploitation of their biological potential; for example D-psicose, only recently available, has been recognized as an important new food. Here we give the definitive and cheap synthesis of 99.4% pure L-glucose from D-glucose which requires purification of neither intermediates nor final product other than extraction into and removal of solvents; a simple crystallization will raise the purity to >99.8%.
Assuntos
Glucose/química , Ácido Glucurônico/síntese química , Ácido Glucurônico/química , Conformação MolecularRESUMO
Crystal structures were obtained for the two C2 epimeric azido-γ-lactones 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-ido-heptono-1,4-lactone and 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-gulo-heptono-1,4-lactone prepared from kinetic and thermodynamic azide displacements of a triflate derived from d-glucoheptonolactone. Azido-γ-lactones are very useful intermediates in the synthesis of iminosugars and polyhydroxylated amino acids. In this study two epimeric azido-heptitols allow biotechnological transformations via Izumoring techniques to 8 of the 16 possible homonojirimycin analogues, 5 of which were isolated pure because of the lack of stereoselectivity of the final reductive amination. A side-by-side glycosidase inhibition profile of 11 of the possible 16 HNJ stereoisomers derived from d-glucose and d-mannose is presented.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Azidas/química , Glucose/química , Lactonas/química , Termodinâmica , 1-Desoxinojirimicina/química , Cinética , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
The formation from D-glucose of both enantiomers of 2,4-dideoxy-2,4-iminoribonic acid is the first chemical synthesis of unprotected 3-hydroxyazetidine carboxylic acids. The long-term stability of 3-hydroxyazetidine amides is established at acidic and neutral pH and implies their value as non-proteinogenic amino acid components of peptides, providing medicinal chemists with a new class of peptide isosteres. The structure of N,3-O-dibenzyl-2,4-dideoxy-2,4-imino-D-ribonic acid was established by X-ray crystallographic analysis. An N-methylazetidine amide derivative is a specific inhibitor of ß-hexosaminidases at the micromolar level, and is only the second example of potent inhibition of any glycosidase by an amide of a sugar amino acid related to an iminosugar.
Assuntos
Aminoácidos/química , Ácido Azetidinocarboxílico/química , Azetidinas/química , Amidas/química , Animais , Ácido Azetidinocarboxílico/síntese química , Ácido Azetidinocarboxílico/metabolismo , Azetidinas/síntese química , Azetidinas/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Hexosaminidases/antagonistas & inibidores , Hexosaminidases/metabolismo , Humanos , Imino Açúcares/química , Conformação Molecular , Ligação Proteica , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Ring closure of a 3,5-di-O-triflate derived from D-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine.
Assuntos
Azetidinas/síntese química , Hexoses/química , Manitol/análogos & derivados , Polímeros/síntese química , Swainsonina/análogos & derivados , Swainsonina/síntese química , Azetidinas/química , Ciclização , Imino Furanoses/síntese química , Imino Furanoses/química , Manitol/síntese química , Manitol/química , Manosidases/antagonistas & inibidores , Estrutura Molecular , Polímeros/química , Sorbitol/análogos & derivados , Relação Estrutura-Atividade , Swainsonina/químicaRESUMO
The efficient scalable syntheses of 2-acetamido-1,2-dideoxy-D-galacto-nojirimycin (DGJNAc) and 2-acetamido-1,2-dideoxy-D-gluco-nojirimycin (DNJNAc) from D-glucuronolactone, as well as of their enantiomers from L-glucuronolactone, are reported. The evaluation of both enantiomers of DNJNAc and DGJNAc, along with their N-alkyl derivatives, as glycosidase inhibitors showed that DGJNAc and its N-alkyl derivatives were all inhibitors of α-GalNAcase but that none of the epimeric DNJNAc derivatives inhibited this enzyme. In contrast, both DGJNAc and DNJNAc, as well as their alkyl derivatives, were potent inhibitors of ß-GlcNAcases and ß-GalNAcases. Neither of the L-enantiomers showed any significant inhibition of any of the enzymes tested. Correlation of the in vitro inhibition with the cellular data, by using a free oligosaccharide analysis of the lysosomal enzyme inhibition, revealed the following structure-property relationship: hydrophobic side-chains preferentially promoted the intracellular access of iminosugars to those inhibitors with more-hydrophilic side-chain characteristics.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Acetamidas/química , Acetamidas/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glucuronatos/química , Hexosaminidases/antagonistas & inibidores , Hexosaminidases/química , Imino Piranoses/química , Oligossacarídeos/química , 1-Desoxinojirimicina/síntese química , 1-Desoxinojirimicina/química , Alquilação , Interações Hidrofóbicas e Hidrofílicas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
X-ray crystallography defines the relative configuration at the three-stereogenic centres in the title compound N-benzyl-l-XYLNAc, C(14)H(20)N(2)O(3). The five-membered pyrrolidine ring adopts an envelope conformation with the N atom lying out of the plane of the other four atoms. In the crystal structure, inter-molecular O-Hâ¯O, N-Hâ¯O and O-Hâ¯N hydrogen bonds link the mol-ecules into chains along [100]. The carbonyl group O atom acts as an acceptor for a bifurcated hydrogen bond. The absolute configuration is determined by the use of l-glucuronolactone as the starting material for the synthesis.