Synthesis and evaluation of scutellarein derivatives with improved neuroprotective activity and aqueous solubility

Oxidative stress caused cell damage is considered the primary pathogenic mechanism of cerebral ischemia-reperfusion injury (CIRI). Scutellarein is a natural flavonoid compound with excellent antioxidant and anti-inflammatory activities, which could be developed as a promising neuroprotective agent, but its poor water solubility limits its clinical application. To improve the water solubility of scutellarein and enhance its activity further, phosphate or phosphonate groups was introduced, thus six scutellarein derivatives were designed and synthesized. The water solubility and neuroprotective effects of these derivatives were evaluated. Among them, compound 12b exhibited more potent cytoprotective effect and water solubility than the lead compound scutellarein. Mechanism studies revealed that compound 12b could prevent H₂O₂ induced neuronal apoptosis, significantly decrease ROS generation, reduce MDA and elevate SOD levels in a dose-dependent manner. Furthermore, western blot assay disclosed that compound 12b could activate Nrf2 and increase the expression of its downstream genes HO-1 in a concentration-dependent manner, thus displaying potent neuroprotective activity. In summary, the phosphonate derivative 12b not only has excellent water solubility but also superior cytoprotective activity, making it a promising neuroprotective agent worthy of further development.