α-Glucosidase Inhibitors from Ageratina grandifolia

Abstract

Fractionation of an aqueous extract from the aerial parts of Ageratina grandifolia yielded a new natural product, namely, 4-hydroxy-3-((S)-1′-angeloyloxy-(R)-2′,3′-epoxy-3′methyl)butylacetophenone (1), along with eight known compounds, including three flavonoids (2−4) and five chromenes (5− 9). NMR data interpretation and DFT-calculated chemical shifts combined with DP4+ statistical and J-DP4 probability analyses allowed for the complete characterization of compound 1. The presence of compound 1 in a plant that biosynthesizes 2,2dimethylchromenes is noteworthy, because an epoxy derivative has long been postulated as the reaction intermediate from the prenylated p-hydroxyacetophenones to cyclic dimethylchromenes. So far, this key intermediate has not been isolated, due to its purported chemical instability. Thus, this is the first report of a potential epoxide intermediate, leading to any of the chromene constituents of this plant. Compounds 1−9 inhibited yeast α-glucosidase with IC 50 values ranging from 0.79 to 460 μM (acarbose, IC 50 = 278.7 μM). The most active compounds were quercetagetin-7-O-(6-O-caffeoyl-β-D-glucopyranoside (3) and 6hydroxykaempferol-7-O-(6-O-caffeoyl-β-D-glucopyranoside (4). Kinetic analysis of 3 revealed its mixed-type inhibitor nature. Docking studies into the crystallographic structure of yeast α-glucosidase (pdb 3A4A) predicted that 3 and 4 bind at the catalytic site of the enzyme.

Computational Structural Revision of a 4-Hydroxy-3-(1′-angeloyloxy-2′,3′-epoxy-3′-methyl)butylacetophenone Compound from Ageratina grandifolia

“…Additionally, the 1 H NMR spectrum published by the authors did not seem to show a signal at ∼5.0 ppm, as would be expected for a phenolic moiety. Note that the amount of water in the reported 1 H spectrum, Figure S2 in the Supporting Information of ref , was not particularly high. Even more, the reported 13 C NMR shifts badly fitted their DFT-computed shieldings.…”

“…R ecently, Mata and co-workers reported a new epoxy compound (Figure 1, 1) isolated from Ageratina grandifolia. 1 On the basis of standard 1D and 2D NMR experiments, the authors proposed that 1 should be the 4hydroxy-3-(1′ -angeloyloxy-2′,3′-epoxy-3′ -methyl)butylacetophenone shown in Figure 1. The structure was particularly relevant since it would provide evidence for the involvement of an epoxide intermediate in the biosynthesis of 2,2-dimethylchromenes or benzofurans from prenylated phydroxyacetophenones.…”

“…Recently, Mata and co-workers reported a new epoxy compound (Figure , 1 ) isolated from Ageratina grandifolia . On the basis of standard 1D and 2D NMR experiments, the authors proposed that 1 should be the 4-hydroxy-3-(1′-angeloyloxy-2′,3′-epoxy-3′-methyl)­butylacetophenone shown in Figure .…”

“…Top: Putative structure 1 from ref and the herein proposed chromane structure 2 . Bottom: Trial diastereoisomeric structures for 2 .…”

“…The authors, however, made an important conceptual mistake when claiming to be able to distinguish between enantiomeric structures only on the basis of the reported shifts and couplings. The different scores obtained for the (1′ S ,2′ R )- 1 and (1′ R ,2′ S )- 1 forms could probably be attributed to undersampling in the conformational search step, which led to slightly different numbers in the DP4/J-DP4 computations (see Table S1 in the Supporting Information of ref ).…”