Polyphosphoric acid-promoted one-pot synthesis and neuroprotective effects of flavanones against NMDA-induced injury in PC12 cells

Abstract

We report herein an efficient polyphosphoric acid (PPA) promoted one-pot protocol for the synthesis of flavanone derivatives from 2-hydroxyacetophenones and benzaldehydes. A variety of flavanones were produced in moderate to excellent yields and evaluated for their neuroprotective effects against N-methyl-d-aspartate (NMDA)-induced excitotoxicity in PC12 cells. Derivatives bearing electron-donating groups exhibited better neuroprotective activity. Compound 3m demonstrated the best protective potency and reversed the intracellular calcium (Ca²⁺) influx caused by NMDA, suggesting that flavanones protected the PC12 cells against NMDA-induced neurotoxicity via inhibition of Ca²⁺ overload.

Scheme 1. (a) One-pot approaches for the synthesis of flavanones. (b) One-pot synthesis of (E)-3-benzylideneflavanones. (c) This work.

Fig. 1. Kinetic of the formation of flavanone 3a.

Scheme 2. Plausible mechanism.

Fig. 2. Protective and Ca²⁺ antagonistic effects of flavanones on NMDA-induced injury in PC12 cells. (A) Protective effects of MK-801 and flavanones at 20 μM. (B) Concentration-dependent protective effects of compound 3m. (C) Blue fluorescence shown the Ca²⁺ influx. Cytotoxicity was measured by MTT assay. Data are presented as mean ± SD (n = 3). ^###p < 0.001 as compared to control group, *p < 0.05, **p < 0.01, ***p < 0.001 as compared to NMDA group.

Fig. 3. Docking of compound 3m with glycine binding site of NMDA receptor (PDB: 4NF4). (A) Alignment of (2R)-3m (green), (2S)-3m (gray) and co-crystallized ligand DCKA (yellow) in the active site. The interactions of (2R)-3m (B) and (2S)-3m (C) with the active site residues. Hydrogen bond interactions were shown in yellow dotted lines. 2D diagram of (2R)-3m (D) and (2S)-3m (E) interactions with the active site residues.