Calmodulin-Targeting Molecules from Ageratina grandifolia.

Four new natural chemical entities, including 2-hydroxy-α-truxillic acid (2), (3R,4S)-2,2-dimethyl-3-hydroxy-4-(1-angeloyloxy)-6-acetyl-7-methoxychromane (3), N-tricosanoyltyramine (4), and grandifolamide (5), were isolated along with 11 known compounds (1, 6-15) from the aerial parts of Ageratina grandifolia. The chemical structures were elucidated using chemical derivatization and HR-MS, NMR, and DFT-calculated chemical shifts, combined with DP4+ statistical analysis. It was found that 2 decomposed into its biogenetic precursor, o-coumaric acid, upon standing at room temperature for a few weeks. 3,5-Diprenyl-4-hydroxyacetophenone (8), O-methylencecalinol (10), encecalin (11), and encecalinol (12) bound to calmodulin (CaM) with higher affinity than chlorpromazine, a well-known CaM inhibitor. Molecular dynamics studies revealed that the complexes of these compounds with CaM remained stable during the simulation. Altogether these results revealed the therapeutic and research tool potential of compounds 8, 10, 11, and 12.

α-Glucosidase Inhibitors from Ageratina grandifolia.

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 2,2-dimethylchromenes 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 IC50 values ranging from 0.79 to 460 µM (acarbose, IC50 = 278.7 µM). The most active compounds were quercetagetin-7-O-(6-O-caffeoyl-ß-d-glucopyranoside (3) and 6-hydroxykaempferol-7-O-(6-O-caffeoyl-ß-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.