A concise synthesis of N-substituted fagomine derivatives and the systematic exploration of their α-glycosidase inhibition

Fu-xiang Jiang; Qiao-zhen Liu; Dan Zhao; Cui-ting Luo; Cui-ping Guo; Wen-cai Ye; Cheng Luo; Heru Chen

doi:10.1016/j.ejmech.2014.03.004

A concise synthesis of N-substituted fagomine derivatives and the systematic exploration of their α-glycosidase inhibition

Eur J Med Chem. 2014 Apr 22:77:211-22. doi: 10.1016/j.ejmech.2014.03.004. Epub 2014 Mar 3.

Authors

Fu-xiang Jiang¹, Qiao-zhen Liu¹, Dan Zhao², Cui-ting Luo¹, Cui-ping Guo¹, Wen-cai Ye³, Cheng Luo², Heru Chen⁴

Affiliations

¹ Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Huangpu Avenue West 601, Guangzhou 510632, PR China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
³ Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Huangpu Avenue West 601, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China.
⁴ Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Huangpu Avenue West 601, Guangzhou 510632, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China. Electronic address: thrchen@jnu.edu.cn.

PMID: 24642564
DOI: 10.1016/j.ejmech.2014.03.004

Abstract

A novel and concise scheme has been developed successfully for the syntheses of N-substituted fagomine derivatives. The transformation of lactone (2) to 1,5-diol (3) was carried on with high yield (93-95%). The cyclization of 4 to 5 is a high stereoselective reaction (de value > 98%). It is disclosed that bulky substituent at N atom of the piperidine decreases the inhibition activity except those substituents having the ability of solvation or forming disulfide bond with M444 at the active site of α-glycosidase, which enhance the interaction with enzyme. Compounds with S-configuration at C-3 show greater activity than those with R-configuration. The structure-activity relationship study is also supported by molecular docking analysis.

Keywords: Azasugars; Fagomine; Molecular docking; Total synthesis; α-glycosidase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Crystallography, X-Ray
Cyclization
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Glycoside Hydrolase Inhibitors / chemical synthesis
Glycoside Hydrolase Inhibitors / chemistry
Glycoside Hydrolase Inhibitors / pharmacology*
Imino Pyranoses / chemical synthesis
Imino Pyranoses / chemistry
Imino Pyranoses / pharmacology*
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
alpha-Glucosidases / metabolism*

Substances

Enzyme Inhibitors
Glycoside Hydrolase Inhibitors
Imino Pyranoses
fagomine
alpha-Glucosidases