The Research On The Design, Synthesis And Property Of Ginkgolide B Brain Targeting Prodrug

Ginkgolide B (GB) has significant effects on the treatment of ischemic cerebrovascular disease. However due to the presence of the blood-brain barrier, the brain targeting is needed to be further improved. On the basis of preliminary studies in our laboratory, we carried out the design, synthesis and properties of GB brain targeting prodrug based on the chemical delivery system (CDS). Main results are as follows:1. Based on the analysis of GB structure and CDS carrier, we select1,4-dihydro-pyridine and1,4-dihydro-quinoline as carriers and18ester prodrugs of GB (G-01-G-18) is designed.2. Lipid-water partition coefficient (logP) and cerebral blood concentration ratio (BB) of18prodrugs and GB are predicted by means of calculation software, the logP and BB are two important parameters that affect the brain targeting. Considering the numerical results, stability and follow-up research, G-10and G-02were chosen as target molecules. They are both GB esters connecting1,4-dihydropridine carrier, the difference is that the-CH2COOCH3or methyl was connected nitrogen atom of the pyridine ring respectively.3. Using GB and nicotinic acid as starting material, the product were achieved through three step reaction including esterification, salt formation, reduction. Also, the reaction solvents, temperature, reactant molar ratio and other factors were optimized. Finally, G-02and G-10were synthesis and their structures has been confirmed by1H-NMR and IR.4. The study on chemical oxidation of G-02and G-10were conducted. G-02and G-10had better oxidation capacity in the solution of AgNO3and30%H2O2, and H2O2solution has stronger oxidation capacity, the t1/2of G-02and G-10which calculated by linear regression equation was38.5min and17.7min. In the two oxidants, the oxidation capacity of G-10is stronger than G-02, it suggested that G-10had better brain targeting capacity.5. The stability in buffer solution was also studied, the results are as follows: G-02and G-10had certain stability in the phosphate buffer solution with pH5.8or7.4, but pH7.4had better stability, probably because the hydration easily occured in the acidic pH conditions. G-10has better stability than G-02at pH5.8or7.4, this may be associated with the withdrawing carbonyl group near nitrogen atom in G-10which increase its stability.6. We also studied the stability of G-10in biological media such as plasma and brain homogenate. The stability in80%mouse plasma was higher than that in20%mouse brain homogenate. It is suggested that G-10have sufficient time to deliver from blood to the brain, and oxidation is achieved more rapidly in the brain to ensure better brain targeting delivery performance.