期刊
JOURNAL OF ORGANIC CHEMISTRY
卷 80, 期 9, 页码 4501-4515出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.5b00342
关键词
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资金
- Japanese Society for the Promotion of Science (JSPS) [26460143]
- Leverhulme Trust
- National Basic Research Program of China [2011CB808603, 2012CB822101]
- National Natural Science Foundation of China [21272240]
- National Science and Technology Major Projects for Major New Drugs Innovation and Development [2013ZX09508104]
- Development Fund for Collaborative Innovation Center of Glycoscience of Shandong University
- National Engineering Research Center for Carbohydrate Synthesis of Jiangxi Normal University
- Grants-in-Aid for Scientific Research [26460143] Funding Source: KAKEN
This paper identifies the required configuration and orientation of alpha-glucosidase inhibitors, miglitol, alpha-1-C-butyl-DNJ, and alpha-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-pi 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 alpha-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.
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