吡嗪类化合物的合成及其抗血小板凝集活性测试
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摘要
为提高川芎嗪的抗血小板凝集活性,分别以不同的二胺、2,3-丁二酮和硫辛酸为起始原料,采用溴代、水解、环化、氧化、氢化、取代等反应,通过四条路线合成了7个川芎嗪衍生物,其结构经1H NMR、13C NMR及ESI-MS确证。采用Born比浊法初步测试了化合物的体外抗血小板凝集活性,结果显示,化合物1(IC50=0. 26mmol/L)、2(IC50=0. 27mmol/L)和7(IC50=0. 21mmol/L)对由二磷酸腺苷(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(IC50=0. 49mmol/L)。因此,在不改变川芎嗪药效团的前提下对其进行不同程度的环化,能明显提高川芎嗪的抗血小板凝集活性,此研究为后期化合物的结构修饰提供了一定的参考价值。
In order to improve the antiplatelet agglutination activity of ligustrazine,different diamines,2,3-butanedione and lipoic acid were used as starting materials,seven ligustrazine derivatives were synthesized via four routes,including bromination,hydrolysis,cyclization,oxidation,hydrogenation and substitution reaction. Their structures were confirmed by1 H NMR,13 C NMR and ESI-MS,and the in vitro anti-platelet aggregation activities were tested preliminarily by the Born turbidimetric method. The experimental results showed that compounds 1( IC_(50)=0. 26 mmol/L),2( IC_(50)= 0. 27 mmol/L) and 7( IC_(50)= 0. 21 mmol/L) exhibit significant inhibitory activity for adenosine diphosphate( ADP) induced platelet aggregation,which are superior to the lead compound ligustrazine( IC_(50)= 0. 49 mmol/L). Therefore,without changing ligustrazine pharmacophore,cyclization in different degree can obviously improve the antiplatelet agglutination activity of ligustrazine,which has useful reference value for the structure modification of lead compound.
In order to improve the antiplatelet agglutination activity of ligustrazine,different diamines,2,3-butanedione and lipoic acid were used as starting materials,seven ligustrazine derivatives were synthesized via four routes,including bromination,hydrolysis,cyclization,oxidation,hydrogenation and substitution reaction. Their structures were confirmed by1 H NMR,13 C NMR and ESI-MS,and the in vitro anti-platelet aggregation activities were tested preliminarily by the Born turbidimetric method. The experimental results showed that compounds 1( IC_(50)=0. 26 mmol/L),2( IC_(50)= 0. 27 mmol/L) and 7( IC_(50)= 0. 21 mmol/L) exhibit significant inhibitory activity for adenosine diphosphate( ADP) induced platelet aggregation,which are superior to the lead compound ligustrazine( IC_(50)= 0. 49 mmol/L). Therefore,without changing ligustrazine pharmacophore,cyclization in different degree can obviously improve the antiplatelet agglutination activity of ligustrazine,which has useful reference value for the structure modification of lead compound.
引文
[1]马晓兵.临床合理用药杂志,2017,10(30):178~179.
[2]唐利,向毅,杜潇等.心血管病学进展,2016,37(06):672~677.
[3]沈红.现代中西医结合杂志,1999,8(11):1735~1736.
[4] J Zou,P Gao,X Hao et al. Eur. J. Med. Chem.,2018,147:150~162.
[5] M F Zeng,L M Pan,S M Qi et al. Fitoterapia,2013,88:50~75.
[6] T K Kao,Y C Ou,J S Kuo et al. Neurochem. Int.,2006,48(3):166~176.
[7] X R Cheng,L Zhang,J J Hu et al. Cell. Biol. Int.,2006,31(5):438~443.
[8]汪林,王鹏龙,绪扩等.中草药,2013,44(19):2766~2771.
[9]刘庆杰,王伟,白宏英.中国实用神经疾病杂志,2018,21(04):357~360.
[10]张金彦,吉绍长.现代化工,2012,32(5):32~34.
[11] A O Pittet,R Muralidhara. J. Agr. Food Chem.,1974,22(2):273~279.
[12] G B Zhang,F X Wang,J Y Du et al. Org. Lett.,2012,14(14):3696~3699.
[13] K A Parker,A Dermatakis. J. Org. Chem.,1997,62(19):6692~6696.
[14] U Takamitsu,N Hiroaki,W Masashige et al. Tetrahed. Lett.,2006,47:9359~9364.
[15] B Klaus,B Meier. Angew. Chem. Int. Ed.,2006,45:4015~4019.
[16] B R Yeo,A J Hallett,B M Kariuki et al. Polyhedron,2010,29(3):1088~1094.
[17]朱桃,李毅,樊玲玲等.化学试剂,2017,39(4):353~356.
[18]樊玲玲,李毅,吴晓芳等.化学通报,2018,81(6):543~547.
[2]唐利,向毅,杜潇等.心血管病学进展,2016,37(06):672~677.
[3]沈红.现代中西医结合杂志,1999,8(11):1735~1736.
[4] J Zou,P Gao,X Hao et al. Eur. J. Med. Chem.,2018,147:150~162.
[5] M F Zeng,L M Pan,S M Qi et al. Fitoterapia,2013,88:50~75.
[6] T K Kao,Y C Ou,J S Kuo et al. Neurochem. Int.,2006,48(3):166~176.
[7] X R Cheng,L Zhang,J J Hu et al. Cell. Biol. Int.,2006,31(5):438~443.
[8]汪林,王鹏龙,绪扩等.中草药,2013,44(19):2766~2771.
[9]刘庆杰,王伟,白宏英.中国实用神经疾病杂志,2018,21(04):357~360.
[10]张金彦,吉绍长.现代化工,2012,32(5):32~34.
[11] A O Pittet,R Muralidhara. J. Agr. Food Chem.,1974,22(2):273~279.
[12] G B Zhang,F X Wang,J Y Du et al. Org. Lett.,2012,14(14):3696~3699.
[13] K A Parker,A Dermatakis. J. Org. Chem.,1997,62(19):6692~6696.
[14] U Takamitsu,N Hiroaki,W Masashige et al. Tetrahed. Lett.,2006,47:9359~9364.
[15] B Klaus,B Meier. Angew. Chem. Int. Ed.,2006,45:4015~4019.
[16] B R Yeo,A J Hallett,B M Kariuki et al. Polyhedron,2010,29(3):1088~1094.
[17]朱桃,李毅,樊玲玲等.化学试剂,2017,39(4):353~356.
[18]樊玲玲,李毅,吴晓芳等.化学通报,2018,81(6):543~547.