多取代三氮唑类化合物的合成及其抗肿瘤活性研究  

Synthesis and antitumor activity of multisubstituted triazole derivatives

作　　者：文逸宁 刘宁宁[1] 张志峰[1] 陈雪[1] 袁伟媛 张青山[1] 武钦佩[1] 

机构地区：[1]北京理工大学化工与环境学院,北京100081

出　　处：《中国药物化学杂志》2015年第5期348-354,共7页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(21172019)

摘　　要：目的设计合成一系列4-胺甲酰-1,5-双芳基-1,2,3-三氮唑类化合物,并评价其抗肿瘤活性。方法以叠氮化钠为原料,经亲核取代反应制成有机叠氮化物后与丙炔酸甲酯通过Huisgen 1,3-偶极环加成反应得到5-碘代-1,2,3-三氮唑,再与单质硫和苄溴类化合物经3步连续反应"一锅法"得到1-对甲氧基苄基-4-甲氧甲酰-5-苄基硫醚-1,2,3-三氮唑,对三氮唑环上的4-甲氧甲酰基进行胺解反应得到目标化合物。采用MTT法测定目标化合物对人乳腺癌细胞(MCF-7)、肝癌细胞(Hep G2)、肺癌细胞(A549)和宫颈癌细胞(He La)的抑制活性。结果与结论合成了15个未见报道的4-胺甲酰-1,5-双芳基-1,2,3-三氮唑类化合物,其结构经1H-NMR、13C-NMR及HR-MS谱确证。其中,化合物7a对Hep G2、A549和He La细胞均表现出中等程度的抑制活性(IC50值分别为23.00、33.88、26.66μmol·L-1),有进一步研究的价值。The 1,2,3-triazole with its special physiochemical properties shows diverse biological activities. It could be acted as the bioisostere of amide,double bonds and aromatic rings in medicinal chemistry,and could also be the linker of dimer or be used in bioconjugation. A novel series of 4-carboxamide-1,5-diaryl-1,2,3-triazoles were designed by introducing the 1,2,3-triazole moiety as the bioisostere of double bond in combretastatins and combining the 4-carboxamide moiety of antitumor drug carboxyamidotriazole（ CAI）.Fifteen target compounds were synthesized from sodium azide via a total six steps reaction containing azidation,Cu I / NBS catalyzed Huisgen 1,3-dipolar cycloaddition,a one-pot reaction consist of three steps and amidation. Their structures were characterized by1H-NM R,13C-NM R and HR-M S. The antiproliferative effects in four human tumor cell lines in vitro were tested by M TT assay. Among them,compound 7a（ R =H） showmoderate activity against Hep G2,A549 and He La cell lines with IC50 values 23. 00 μmol·L^-1,33. 88 μmol·L^-1and 26. 66 μmol·L^-1respectively. Structure-activity relationships revealed that the introduction of cyclopropyl on the 4-carboxamide could improve the activity but the electron withdrawing group on the 5-benzylthio could resulted in the opposite effect.

关 键 词：1 2 3-三氮唑 化学合成 抗肿瘤活性 

分 类 号：R914.5[医药卫生—药物化学]