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Closed Access item Synthesis and Comparative Glycosidase Inhibitory Properties of Reducing Castanospermine Analogues

Authors:Díaz Pérez, Paula
García Moreno, María Isabel
Ortiz-Mellet, Carmen
García-Fernández, José Manuel
Keywords:Carbamates, Castanospermine, Inhibitors, Thiocarbamates, Indolizidines, Enzymes
Issue Date:2-Jun-2005
Citation:European Journal of Organic Chemistry (14): 2903-2913 (2005)
Abstract:The feasibility of the intramolecular nucleophilic addition of the nitrogen atom in cyclic (thio)carbamates with a pseudo-C-nucleoside structure to the masked carbonyl group in aldose precursors in the synthesis of reducing (i.e., 5-hydroxy)6-oxaindolizidine frameworks is illustrated by the preparation of the 6-epi, 7-epi, 8-epi and 6,8a-di-epi diastereomers of the potent glycosidase inhibitor (+)-castanospermine. In all cases, the increased anomeric effect caused by the high sp2 character of the pseudoamide-type nitrogen atom resulted in the pseudoanomeric hydroxy group being anchored in an axial orientation in aqueous solution, as in the aglycons in α-glycosides. These analogs of the natural alkaloid showed a higher selectivity in the inhibition of α-glucosidases. Structure/glycosidase inhibitory activity studies indicated that inversion of any hydroxy group resulted in a dramatic decrease in the inhibition potency, confirming the critical importance of a correct hydroxylation profile. In the case of (+)-8-epi-6-oxacastanospermine derivatives, with a hydroxylation profile with a structural complementarity to that of D-galactose, a moderate but very selective inhibition of α-galactosidase was observed, supporting the importance of a defined configuration at pseudoanomeric centres for anomeric specificity.
Description:11 páginas, 2 figuras, 1 tabla, 4 esquemas.
Publisher version (URL):http://dx.doi.org/10.1002/ejoc.200500071
E-ISSNmetadata.dc.identifier.doi = DOI:1099-0690
Appears in Collections:(IIQ) Artículos

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