1. Design and Synthesis of Labystegines, Hybrid Iminosugars from LAB and Calystegine, as Inhibitors of Intestinal α-Glucosidases: Binding Conformation and Interaction for ntSI.
- Author
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Kato A, Zhang ZL, Wang HY, Jia YM, Yu CY, Kinami K, Hirokami Y, Tsuji Y, Adachi I, Nash RJ, Fleet GW, Koseki J, Nakagome I, and Hirono S
- Subjects
- 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 chemistry, Drug Design, Enzyme Inhibitors pharmacology, Imino Sugars pharmacology, Nortropanes pharmacology, Sucrase antagonists & inhibitors, alpha-Glucosidases metabolism
- 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.
- Published
- 2015
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