PEG-scutellarin prodrugs: synthesis, water solubility and protective effect on cerebral ischemia/reperfusion injury.
ABSTRACT Fifteen PEG-scutellarin prodrugs were synthesized by modifying carboxyl and phenolic hydroxyl groups of scutellarin with mPEG of different molecular weight (400-3000). The water solubility of prodrugs increased remarkably and reached the maximum value of 783.88 mg/mL (scutellarin, 0.02 mg/mL). The anti-infarct effects of four PEG prodrugs with high water solubility were evaluated by Cerebral Ischemia/Reperfusion in the Middle Cerebral Artery Occlusion (MCAO) model. The results showed that the prodrug 7e could significantly reduce the infarct area from 27.2% to 12.2% (33.3% for the control) and decrease the neurological deficit score from 2.77 to 1.32 (2.85 for the control). The half-life (18.62 min) of the prodrug 7e was significantly longer than that of scutellarin (3.03 min).
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ABSTRACT: This study was to determine tissue distribution and pharmacokinetics of mPEG-scutellarin prodrug (7e), a chemical entity previously shown to have a beneficial effect in cerebral ischemia/reperfusion (I/R) injury. After injecting scutellarin or prodrug 7e, the concentrations of scutellarin and 7e in tissues were determined and the pharmacokinetic parameters were calculated. The results showed that the distribution of scutellarin in tissues was enhanced by PEGylation. The distribution of 7e in brain was approximately 2.1-fold higher than that of scutellarin, indicating that PEGylation increased the brain penetration of scutellarin. We conclude that 7e could exert more effective protection on cerebral I/R injury in mice. This study also provided a simple and convenient strategy to identify novel drugs with potential protective function for I/R injury in mice.Acta Pharmaceutica Sinica B. 06/2012; 2(3):274–277.