title: Synthesis and biological evaluation of phosphorylated flavonoids as potent and selective inhibitors of cholesterol esterase.
abstract: A series of phosphorylated flavonoids were synthesized and investigated in vitro as inhibitors of pancreatic cholesterol esterase (CEase) and acetylcholinesterase (AChE). The results showed that most of the synthesized compounds exhibited nanomolar potency against CEase, much better than the parent flavonoids. Furthermore, these phosphorylated flavonoids demonstrated good to high selectivity for CEase over AChE, which only showed micromolar potency inhibition of AChE. The most selective and potent inhibitor of CEase (3e) had IC₅₀ value of 0.72 nM and 11800-fold selectivity for CEase over AChE. The structure-activity relationships revealed that the free hydroxyl group at position 5 and phosphate group at position 7 of the phosphorylated flavonoids are favorable to the inhibition of CEase. The inhibition mechanism and kinetic characterization studies indicated that they are irreversible competitive inhibitors of CEase.
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, 135 Xingangxi Lu, Guangzhou 510275, China.
authors.forename: Yingling
authors.initials: Y
authors.lastname: Wei
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, 135 Xingangxi Lu, Guangzhou 510275, China. Electronic address: cespay@mail.sysu.edu.cn.
authors.forename: Ai-Yun
authors.initials: AY
authors.lastname: Peng
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, 135 Xingangxi Lu, Guangzhou 510275, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, 135 Xingangxi Lu, Guangzhou 510275, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: College of Bioscience and Biotechnology, Hunan Agricultural University, Furong District, Changsha 410428, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Peng
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, 135 Xingangxi Lu, Guangzhou 510275, China.
authors.forename: Yidan
authors.initials: Y
authors.lastname: Du
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, 135 Xingangxi Lu, Guangzhou 510275, China.
authors.forename: Jingming
authors.initials: J
authors.lastname: Tang
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D010766:Phosphorylation; D021241:Spectrometry, Mass, Electrospray Ionization; D002787:Sterol Esterase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D002787:Sterol Esterase
keywords: Acetylcholinesterase; Cholesterol esterase; Inhibitor; Organophosphate; Phosphorylated flavonoids; Selectivity