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Design and Synthesis of Labystegines, Hybrid Iminosugars from LAB and Calystegine, as Inhibitors of Intestinal α-Glucosidases: Binding Conformation and Interaction for ntSI.
- Source :
-
The Journal of organic chemistry [J Org Chem] 2015 May 01; Vol. 80 (9), pp. 4501-15. Date of Electronic Publication: 2015 Apr 13. - Publication Year :
- 2015
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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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1520-6904
- Volume :
- 80
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of organic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25843107
- Full Text :
- https://doi.org/10.1021/acs.joc.5b00342