Abstract
Merrillianoid (1), a racemic neolignan possessing the characteristic benzo-2,7-dioxabicyclo[3.2.1]octane moiety, was isolated from the branches and leaves of Illicium merrillianum. Chiral separation of 1 gave two enantiomers (+)−1 and (−)−1. The structure of 1 was established by comprehensive spectroscopic analysis and single crystal X-ray diffraction. The absolute configurations of enantiomers were determined by quantum mechanical calculation. Compound (+)−1 exhibited a better neurotrophic activity than racemate 1 by promoting nerve growth factor (NGF) induced PC12 cell neurite outgrowth, while (−)−1 showed a distinctive inhibitory effect. Furthermore, a mechanism study indicated that the two enantiomers influenced NGF-induced neurite outgrowth of PC12 cells possibly by interacting with the trkA receptor, and extracellular signal regulated kinases 1/2 (ERK1/2) and mitogen-activated protein kinase (MEK) in Ras/ERK signal cascade. But the phosphorylation level of serine/threonine kinase Akt1 and Akt2 in PI3K/Akt signal pathway showed no significant difference between (+)−1 and (−)−1.
Highlights
Cells[10,11], we investigated the influence of compounds on the phosphorylation of associated proteins in Ras/ERK and PI3K/Akt pathway
The phosphorylation level of serine/threonine kinase Akt[1] and Akt[2] in PI3K/Akt pathway showed no significant difference between (+ )− 1 and (− )− 1. These findings provided a pair of interesting neolignans for Nerve growth factor (NGF)-agonist and antagonist drug design, and revealed that absolute configurations dramatically affected biological activities of compounds
Because of the rigid structure of 1 and the relative configuration established by NOESY experiment and single crystal X-ray diffraction, the arbitrarily assigned absolute configuration of 7R,8S,7′ S,8′ S for (+ )− 1 was geometrically optimized by using density functional theory (DFT) at B3LYP/3-21G level to afford three preffered conformers A–C (Δ E < 5.0 kJ/mol) (Fig. 4)
Summary
Compound 1 was obtained as colorless needle crystal. The IR spectrum displayed absorptions due to the C− O bands at 1033, 1203 cm−1, and the phenyl groups at 1464, 1508 cm−1. Because of the rigid structure of 1 and the relative configuration established by NOESY experiment and single crystal X-ray diffraction, the arbitrarily assigned absolute configuration of 7R,8S,7′ S,8′ S for (+ )− 1 was geometrically optimized by using density functional theory (DFT) at B3LYP/3-21G level to afford three preffered conformers A–C (Δ E < 5.0 kJ/mol) (Fig. 4). Despite having the same planar structure, the opposite absolute configurations for (+ )− 1 and (− )− 1 resulted in distinctive effects on NGF-induced PC12 cell differentiation. (+ )− 1 was found to have a better effect than racemate 1 in promoting NGF-induced neurite outgrowth of PC12 cells possibly by increasing the phosphorylation level of TrkA receptor, and MEK, ERK1/2 in Ras/ERK signaling cascade at concentrations of 1–10 μ M, while its enantiomer (− )− 1 played the opposite role at the same concentrations. The results reported in this paper offer a pair of interesting neolignan enantiomers for potential NGF agonist and antagonist drug development
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