title: Synthesis of xanthone derivatives with extended pi-systems as alpha-glucosidase inhibitors: insight into the probable binding mode.
abstract: A series of novel xanthone derivatives with extended pi-systems, that is, benzoxanthones 2-4, and their structurally perturbed analogs 5-9 have been designed and synthesized as alpha-glucosidase inhibitors. Their inhibitory activities toward yeast's alpha-glucosidase were evaluated with the aim to enrich the structure-activity relationship. The results indicated that benzoxanthones 2-4 were capable of inhibiting in vitro yeast's alpha-glucosidase 17- to 28-fold more strongly than xanthone derivative 1 that has smaller conjugated pi-system. Benzoxanthone 8, bearing angularly fused aromatic rings, and reduced benzoxanthone 5 showed decreased activities, strongly suggesting that linearly conjugated pi-systems play a crucial role in the inhibition process. O-Methylation of 3-OH of benzoxanthone 2 and nitration at C4 position led to a large decrease in the activity. This indicates that 3-OH of benzoxanthone was crucial to the inhibitory activity, primarily as an H-bonding donor. The present results suggest that pi-pi stacking effect and H-bonding make substantial contributions to elicit the inhibitory activities of this general class of inhibitors.
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.forename: Wen-Hua
authors.initials: WH
authors.lastname: Chen
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Zun-Le
authors.initials: ZL
authors.lastname: Xu
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007202:Indicators and Reagents; D014970:Xanthines