Chiral resolution and bioactivity of enantiomeric furofuran lignans from Juglans mandshurica Maxim

Abstract Enantiomers have generally been reported mostly for racemic mixtures with a 1:1 ratio, as in that case there were weak Cotton effects in the ECD spectrum and negligible optical rotations. A furofuran lignan (sesamin), with a remarkable rotation and significant Cotton effects, was isolated from Juglans mandshurica Maxim. Subsequently, sesamin was resolved by chiral HPLC to afford a pair of enantiomers, (+)-sesamin (a) and (−)-sesamin (b), in a ratio of approximately 1:3. Their absolute configurations were determined by computational analysis of their electronic circular dichroism (ECD) spectrum. In addition, the pair of enantiomers were evaluated for the inhibition of self-induced Aβ aggregation. Interestingly, (+)-sesamin (a) (67.7%) and (−)-sesamin (b) (80.6%) exhibited different degrees of anti-Aβ aggregation activity. The different inhibition profiles were further explained by molecular dynamics and docking simulation study. Graphical Abstract


Introduction
In nature, lignans with chiral carbon atoms are usually composed of a pair of enantiomers or several pairs of stereoisomers with different amount (Pereira et al. 2011). In general, biological effects of enantiomers are not identical owing to the chiral nature of the biological receptors (Crossley 1995). It is essential to obtain optically pure compounds and evaluate their pharmacological effects. Herein, chiral column chromatography analysis is regarded as a powerful and effective method to obtain pure enantiomers.
Juglans mandshurica Maxim., belonging to the Juglans genus of the Juglandaceae family, is widely distributed in China and Korea (Chen et al. 2015;Diao et al. 2017;Jiang et al. 2017). In our present study, a furofuran lignan (sesamin) was obtained as a scalemic mixture from J. mandshurica that was resolved by HPLC analysis using a chiral column to afford a pair of enantiomers. The inhibitory activity on Ab aggregation of optical pure compounds was tested by ThT assay.
To explore the interaction of the enantiomers in structural terms, molecular dynamics simulations were performed using the GROMACS5 simulation package to relax the structure and dynamics of protein (Manouchehri et al. 2016). The result was used for further docking simulations. Analysis for optimized binding conformation of (À)-sesamin (b) in Figure 1 displayed that methylenedioxy group interacts with Lys16 residue and the Leu17 residue of Ab 1-42 via hydrogen bonding (distance 2.76 Å, 1.96 Å). However, (þ)-sesamin (a) can only interact with Ser26 residue through a hydrogen bond with a distance of 2.42 Å. In addition, Lys16 (Yu et al. 2019) and Leu17 (Liu et al. 2004) were also considered as key active residues interacting with natural ligands. Overall, the results in docking study were consistent with ThT assay, and further proved that (À)-sesamin (b) showed optical selectivity on Ab 1-42 aggregated inhibition.

Conclusions
In this paper, a pair of furofuran lignan enantiomers, (þ)-sesamin (a) and (À)-sesamin (b), were successfully achieved with a ratio of 1:3 by a chiral chromatographic column. Interestingly, this pair of enantiomers exhibited the influence of different stereochemistries on anti-Ab aggregation activity. This work described here will be of particular value for the enantioselectivity of furofuran lignans.

Disclosure statement
No potential conflict of interest was reported by the authors.