Studies On Structure Modifying Of Ligustrazing And Bioactivities Of Ligustrazine's Derivatives

Ligustrazine (Tetramethylpyrazine) is an active constituent of Ligustracum chuanxiong. There are many reports on its extraction, separation and synthesis in the references. As a remarkably effective drug, pharmacology and utility of ligustrazine have been extensively demonstrated in recent years. It could inhibit platelet aggregation, prevent thrombus from forming, and so on. However, its potential usage is limited because of its poor water solubility, quick metabolism, short half-life and low utilization ratio. It is necessary and important to find the new ligustrazine's analogues better in pharmacology.In chapter 1 of this thesis, the relationship between the structure and effect of medicines and the traditional approaches of structure modifying are reviewed, as well as the pharmacological activities, clinical applications and structure modifying of ligustrazine.Chapter 2 contains the studies on synthesis and bioactivities of the derivatives of ligustrazine. In order to improve solubility of ligustrazine and find its better analogues in bioactivity, based on the compatibility of medicines, thirteen derivatives of ligustrazine are obtained. Eight compounds are firstly reported. Their structures are identified by element analysis, IR spectroscopy and other characterization methods. The experiments on the solubility of ligustrazinates have been done. All the results suggest that the solubility of modified ligustrazinates is better than that of unmodified due to the bonding with hydrophilic groups. In addition, the condition of synthesis of tetramethylpyrazine -mono-N-oxide is discussed. Tetramethylpyrazine-mono-N-oxide obtained is in a good yield, when tetramethylpyrazine is heated with 2 molar equivalents of 30% hydrogen peroxide in 5 molar equivalents of glacial acetic acid for a total of 12 hours at 70℃. The experiments on bioactivity of the compounds consist of anti-oxidative activity and platelet aggregation inhibiting. The results indicate that O2- produced in AP-TEMED system can be scavenged by the compound T-4 at aconcentration of 1 × 10-2 M. The compound T-4 shows significant effect in scavenging · OH which is produced in H2O2/Fe2+ system at a concentration of 1 × 10-2 M. The compound T-6 also shows evident effect in scavenging ·OH at a concentration of 5×10-3 M. All of four compounds studied can inhibit rabbit's platelet aggregation induced by ADP in the platelet aggregation inhibited experiment.