ABSTRACT
This paper identifies the required configuration and orientation of α-glucosidase inhibitors, miglitol, α-1-C-butyl-DNJ, and α-1-C-butyl-LAB for binding to ntSI (isomaltase). Molecular dynamics (MD) calculations suggested that the flexibility around the keyhole of ntSI is lower than that of ctSI (sucrase). Furthermore, a molecular-docking study revealed that a specific binding orientation with a CH-π interaction (Trp370 and Phe648) is a requirement for achieving a strong affinity with ntSI. On the basis of these results, a new class of nortropane-type iminosugars, labystegines, hybrid iminosugars of LAB and calystegine, have been designed and synthesized efficiently from sugar-derived cyclic nitrones with intramolecular 1,3-dipolar cycloaddition or samarium iodide catalyzed reductive coupling reaction as the key step. Biological evaluation showed that our newly designed 3(S)-hydroxy labystegine (6a) inherited the selectivity against intestinal α-glucosidases from LAB, and its inhibition potency was 10 times better than that of miglitol. Labystegine, therefore, represents a promising new class of nortropane-type iminosugar for improving postprandial hyperglycemia.
Subject(s)
Drug Design , Enzyme Inhibitors/pharmacology , Imino Sugars/pharmacology , Nortropanes/pharmacology , Sucrase/antagonists & inhibitors , alpha-Glucosidases/metabolism , Arabinose/chemistry , Binding Sites/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Imino Furanoses/chemistry , Imino Sugars/chemical synthesis , Imino Sugars/chemistry , Intestines/enzymology , Molecular Conformation , Molecular Dynamics Simulation , Nortropanes/chemical synthesis , Nortropanes/chemistry , Sucrase/metabolism , Sugar Alcohols/chemistry , Tropanes/chemistryABSTRACT
(-)-Erycibelline, the dihydroxynortropane alkaloid isolated from Erycibe elliptilimba Merr. et Chun., was synthesized using a cyclic nitrone as advanced intermediate, wherein the key step was the SmI(2)-induced intramolecular reductive coupling of cyclic nitrone with aldehyde which resulted in good yield and stereoselectivity.