川芎嗪与丁苯酞及花椒毒醇拼合衍生物的合成及抗凝活性研究

Synthesis and anticoagulating activity of ligustrazine,butylphthalide and xanthotoxin hybrids

为获得具有优异抗血小板凝集活性的新化合物,以丁苯酞、川芎嗪为起始原料,经硝化、还原、桑德迈尔反应、酯化和醚化反应合成了9个川芎嗪与丁苯酞、花椒毒酚拼合衍生物。目标化合物结构经~1H-NMR、C-NMR和HRMS确证。并采用Born比浊法初步测试了化合物对二磷酸腺苷(ADP)和花生四烯酸(AA)所诱导的血小板凝集的抑制活性,结果显示化合物2f(IC_(50)=1.39 mmol·L^(-1))、2g(IC_(50)=1.15 mmol·L^(-1))、2h(IC_(50)=1.06 mmol·L^(-1))和2i(IC_(50)=1.13 mmol·L^(-1))对ADP诱导的血小板凝集具有一定的抑制活性,优于先导化合物川芎嗪(IC_(50)=3.37 mmol·L^(-1))和丁苯酞(IC_(50)=1.67 mmol·L^(-1))。化合物2f(IC_(50)=0.81 mmol·L^(-1))、2g(IC_(50)=0.54 mmol·L^(-1))、2h(IC_(50)=0.35 mmol·L^(-1))和2i(IC_(50)=0.99 mmol·L^(-1))对AA诱导的血小板凝集具有优良的抑制活性。可见,将川芎嗪与丁苯酞、花椒毒酚通过酯/酰胺键拼接可显著提高其抗血小板凝集活性。

In order to obtain novel compounds with excellent antiplatelet agglutination activity,the ligustrazine and butylphthalide were used as starting materials,nine ligustrazine derivatives were synthesized by nitration,reduction,Sandmeyer reaction,esterification and etherification reaction.Their structures were characterized by~1HNMR,CNMR and ESI-MS,and anti-platelet aggregation activity had been preliminarily tested by the Born turbidimetric method in vitro.The results showed that compounds 2 f(IC_(50)=1.39 mmol·L^(-1)),2 g(IC_(50)=1.15 mmol·L^(-1)),2 h(IC_(50)=1.06 mmol·L^(-1))and 2 i(IC_(50)=1.13 mmol·L^(-1))exhibited significant inhibitory activity against ADP-induced platelet aggregation comparison with the lead compounds ligustrazine(IC_(50)=3.37 mmol·L^(-1))and butylphthalide(IC_(50)=1.67 mmol·L^(-1)).Compounds 2 f(IC_(50)=0.81 mmol·L^(-1)),2 g(IC_(50)=0.54 mmol·L^(-1)),2 h(IC_(50)=0.35 mmol·L^(-1))and 2 i(IC_(50)=0.99 mmol·L^(-1))displayed moderate inhibitory activity against AA-induced platelet aggregation.Therefore,it could be seen that splicing ligustrazine with butylphthalide or xanthoxytoxin through ester/amide bond could significantly improve its anti-platelet aggregation activity.