取代苄基哌嗪类化合物的合成及其蛋白酪氨酸激酶抑制活性的研究
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摘要
目的以取代苄基哌嗪为基本原料,设计合成具有蛋白酪氨酸激酶(PTK)抑制活性的哌嗪类化合物。方法以苯甲酸为初始化合物,合成中间体苯甲酸(2-氯)乙酯,将中间体分别与15种取代苄基哌嗪进行反应,合成目标化合物。采用酶联免疫吸附法(ELISA)测定PTK抑制活性并计算抑制率,筛选出具有抑制PTK活性的化合物。结果合成苄基哌嗪类化合物15个,结构经IR、1H NMR、MS和元素分析进行确证。经初步筛选表明化合物3h、3o的PTK抑制活性较高。结论目标化合物合成方法简单,反应温和,原料易得廉价。化合物3h、3o的PTK抑制活性较强。
Objective Using substituted benzyl piperazine as the raw material to design and synthesize new piperazine derivatives with protein tyrosine kinase(PTK)inhibitory activity. Methods Benzoic acid was used as starting compound to synthesize a key intermediate,2-chloroethyl benzoate,and the target compounds were synthesized by further reaction of the key intermediate with different substituted benzyl piperazine derivatives. Enzyme-linked immunosorbent assay(ELISA)was used to test the PTK inhibitory activity of the compounds. Results Fifteen new compounds were synthesized and their structures were verified by IR,1 H NMR,MS,and elemental analysis. The PTK inhibitory activity of 3 h and 3 o was stronger than that of the other compounds. Conclusion The synthetic method is simple,and the raw materials are cheap and readily available. Compounds 3 h and 3 o showed relatively higher PTK inhibitory activities.
Objective Using substituted benzyl piperazine as the raw material to design and synthesize new piperazine derivatives with protein tyrosine kinase(PTK)inhibitory activity. Methods Benzoic acid was used as starting compound to synthesize a key intermediate,2-chloroethyl benzoate,and the target compounds were synthesized by further reaction of the key intermediate with different substituted benzyl piperazine derivatives. Enzyme-linked immunosorbent assay(ELISA)was used to test the PTK inhibitory activity of the compounds. Results Fifteen new compounds were synthesized and their structures were verified by IR,1 H NMR,MS,and elemental analysis. The PTK inhibitory activity of 3 h and 3 o was stronger than that of the other compounds. Conclusion The synthetic method is simple,and the raw materials are cheap and readily available. Compounds 3 h and 3 o showed relatively higher PTK inhibitory activities.
引文
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[2]Brun R,Blum J,Chappuis F,et al.Human African trypanosomiasis[J].Lancet,2010,375(9709):148-159.
[3]唐林,张首国,彭涛,等.芳基苄砜类化合物的合成及其蛋白酪氨酸激酶抑制活性评价[J].国际药学研究杂志,2015,42(3):351-354.
[4]樊睿,班树荣,方莲花,等.新型查耳酮衍生物的合成及其初步抗蛋白酪氨酸激酶(PTKs)活性研究[J].中国药物化学杂志,2011,21(3):178-182.
[5]王勇,龙亚秋.蛋白酪氨酸激酶小分子抑制剂的研究新进展[J].有机化学,2011,31(10):1595-1606.
[6]李欣,高金恒,陈国良.蛋白酪氨酸激酶抑制剂的研究进展[J].沈阳药科大学学报,2011,28(12):1005-1012.
[7]Clark RB,Elbaum D.An orthogonal protection strategy for the synthesis of 2-substituted piperazines[J].Tetrahedron,2007,63(14):3057-3065.
[8]Aggarwal M,Kaur R,Saha A,et al.Evaluation of antiviral activity of piperazine against Chikungunya virus targeting hydrophobic pocket of alphavirus capsid protein[J].Antiviral Res,2017,146:102-111.
[9]Keith JM,Apodaca R,Xiao W,et al.Thiadiazopiperazinyl ureas as inhibitors of fatty acid amide hydrolase[J].Bioorg Med Chem Lett,2008,18(17):4838-4843.
[10]蒋达洪,黄敏.含哌嗪基噻吩并[3,2-d]嘧啶类抗癌试剂的设计与合成[J].化学试剂,2012,34(9):797-799.
[11]Munchhof MJ,Beebe JS,Frey RR,et al.Design and SAR of thienopyrimidine and thienopyridine inhibitors of VEGFR-2 kinase activity[J].Bioorg Med Chem Lett,2004,14(1):21-24.
[12]Dai Yj,Guo Y,Frey RR,et al.Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinsae inhibitors[J].J Med Chem,2005,48(19):6066-6083.
[13]韩光亮,尚念勇,杜冠华.酪氨酸蛋白激酶抑制剂的高通量筛选模型[J].中国药理学通报,2005,21(5):628-631.