Study on Derivatization and Biological Activity of Natural Product Daidzein

A new class of Daidzein derivatives were developed, and their protective effects on neuronal cells and their mechanisms were examined. The protective effects of Daidzein derivatives against oxygen and glucose deprivation/reoxygenation (OGD/R) injury in HT22 cells were evaluated via a Cell Counting Kit 8 (CCK-8) assay. Biomarkers associated with ferroptosis, including changes in reactive oxygen species (ROS), lipid peroxidation, ferrous ion (Fe2+), glutathione (GSH), superoxide dismutase (SOD) and malondialdehyde (MDA) levels, were detected via fluorescent probes and specific kits. In addition, the protein expression levels of glutathione peroxidase 4 (GPX4), recombinant solute carrier family 7, member 11 (SLC7A11 or xCT) and nuclear Factor 2 (Nrf2) were analyzed via Western blotting. The newly synthesized Daidzein derivative outperforms not only its parent compound, especially derivative 3, in improving the viability of OGD/R-treated HT22 cells but also edaravone, a positive control drug. This study further revealed the mechanism of action of derivative 3: reducing the level of ROS and lipid peroxidation induced by OGD/R in HT22 cells, restoring SOD and GSH activities, reducing MDA and Fe2+ accumulation, and increasing the protein expression of GPX4, xCT and Nrf2. Derivative 3 has significant neuroprotective effects, and its mechanism may involve activating the Nrf2/xCT/GPX4 pathway and inhibiting neuronal ferroptosis. This study provides a new perspective for neuroprotection research and a direction for drug development.