title: Synthesis of 3-acyloxyxanthone derivatives as α-glucosidase inhibitors: A further insight into the 3-substituents' effect.
abstract: Considerable interest has been attracted in xanthone and its derivatives because of their important biological activities. In this paper, a series of novel 3-arylacyloxyxanthone derivatives 2a-p were synthesized and evaluated for their biological activities toward α-glucosidase. In comparison to the parent 1,3-dihydroxylxanthone 1a, 3-arylacyloxy derivatives 2a-p with additional aromatic ester groups at 3-position show up to 13.7-fold higher inhibitory activities. In particular, the IC50 values of compounds 2i, 2m, 2p reach 13.3, 10.6, 11.6 μM, respectively. These results suggest that addition of aromatic moieties by esterification at the 3-OH of the parent 1,3-dihydroxylxanthone is an efficient way to increase the inhibition against α-glucosidase. Different from previous multi-hydroxylxanthones, these 3-arylacyloxyxanthone derivatives show efficient inhibitory activities may due to the π-stacking or hydrophobic effects of the additional aromatic moieties rather than the H-bonding donor interaction of 3-OH. Structure-activity relationship analysis shows that the substituents on the additional aromatic ring also influence the inhibition. All the oxygen or nitrogen-containing groups, like hydroxyl, methoxy, methaminyl, and alkylsilyloxy, can enhance the inhibitory activities. In addition, the kinetics of enzyme inhibition measured by using Lineweaver-Burk plots shows that selected compounds 2i, 2m and 2p are non-competitive inhibitors. Docking simulations further support our structure-activity relationship analysis that additional aromatic moieties enhance inhibitory activities via hydrophobic effects. The new developed 3-arylacyloxyxanthone derivatives probably bind with α-glucosidase in an allosteric site different from traditional multi-hydroxylxanthones.
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China.
authors.forename: Gai-Li
authors.initials: GL
authors.lastname: Li
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China.
authors.forename: Chao-Yun
authors.initials: CY
authors.lastname: Cai
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China.
authors.forename: Jia-Yun
authors.initials: JY
authors.lastname: He
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Rao
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: yanliu@gdut.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China. Electronic address: ceswb@mail.sysu.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
mesh_terms: D004305:Dose-Response Relationship, Drug; D065089:Glycoside Hydrolase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000520:alpha-Glucosidases / Q000378:metabolism*
chemical_list: D065089:Glycoside Hydrolase Inhibitors; D044004:Xanthones; D000520:alpha-Glucosidases
keywords: Inhibition kinetics; Inhibitory activity; Xanthone derivatives; α-Glucosidase