title: A concise synthesis of N-substituted fagomine derivatives and the systematic exploration of their α-glycosidase inhibition.
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.
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Huangpu Avenue West 601, Guangzhou 510632, PR China.
authors.forename: Fu-xiang
authors.initials: FX
authors.lastname: Jiang
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Huangpu Avenue West 601, Guangzhou 510632, PR China.
authors.forename: Qiao-zhen
authors.initials: QZ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Huangpu Avenue West 601, Guangzhou 510632, PR China.
authors.forename: Cui-ting
authors.initials: CT
authors.lastname: Luo
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Huangpu Avenue West 601, Guangzhou 510632, PR China.
authors.forename: Cui-ping
authors.initials: CP
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Wen-cai
authors.initials: WC
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: 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.
authors.forename: Heru
authors.initials: H
authors.lastname: Chen
mesh_terms: D018360:Crystallography, X-Ray; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050112:Imino Pyranoses / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D000520:alpha-Glucosidases / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D050112:Imino Pyranoses; C105643:fagomine; D000520:alpha-Glucosidases
keywords: Azasugars; Fagomine; Molecular docking; Total synthesis; α-glycosidase