4_氰基_5_芳基_1H_1_2_省略_唑的合成及酪氨酸激酶抑制活性研究_李文杰.pdfVIP

药学学报 Acta Pharmaceutica Sinica 2009, 44 12 : 1371? 1375 ·1371 · 4-氰基-5-芳基-1H -1, 2, 3-三氮唑的合成及酪氨酸激酶抑制活性研究 1 2 1 1* 李文杰 , 刘素芳 , 陈缵光 , 成志毅 1. 中山大学药学院, 广州 510006; 2. 中山大学公共卫生学院, 广州 510080 摘要: 叠氮化钠悬浮在 DMF 溶剂中与芳基丙炔腈在 90～120 °C 下反应 6～10 h, 得到系列 4-氰基-5-芳基- 1H-1, 2, 3-三氮唑化合物, 共 13 个。化合物结构经质谱、1H NMR 、红外光谱等确证, 并用单晶 X 射线衍射测定 了化合物 3f 和 3m 的晶体结构, 两个结构都表明三氮唑的活泼 H 在 1-N 原子上。活性试验表明该系列三氮唑对 HER2 过表达的乳腺癌细胞的增值有抑制活性, 并发现这些化合物对其细胞中HER2 磷酸化的抑制活性与其对细 胞增值的抑制活性明显相关。其中 3k 和 3l 对细胞中酪氨酸激酶磷酸化的半抑制率 IC50 的最低浓度分别为 9.7 μmol·L?1 和 6.6 μmol·L?1 。三氮唑芳基上取代基的吸电子效应对其抑制乳腺癌细胞增值的活性有利。 关键词: 4-氰基-5-芳基-1H-1, 2, 3-三氮唑; 晶体结构; 生物活性 中图分类号: R916.1 文献标识码: A 文章编号: 0513-4870 2009 12-1371-05 Synthesis of 5-aryl-4-cyano-1H-1, 2, 3-triazoles and biological evaluation of their inhibitory action on tyrosine kinase 1 2 1 1* LI Wen-jie , LIU Su-fang , CHEN Zuan-guang , CHENG Zhi-yi 1. School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006, China; 2. School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China Abstract : 5-Aryl-4-cyano-1H-1, 2, 3-triazoles bearing a variety of substituting groups on 5-phenyl were synthesized. Their structures were established by MS, IR and 1H NMR spectra. The crystal structures of compounds 3f and 3m were determined by X-ray diffraction analysis. The active H of the triazole was on 1-N from the crystal structures. The compounds, designed as HER2 tyrosine kinase inhibitors, were screened for bioactivity of growth-inhibition of breast cancer MDA-MB-453 cells. The lowest IC50 value of inhibiting HER2 tyrosine kinase phosphorylation in breast cancer cells is 6.6 μmol·L?1. The inhibiting-growth of breast cancer cells was enhanced from electron-drawing groups joining 5-phenyl on the triazole. Key words: 5-aryl-4-cyano-1H-1, 2, 3-triazole; crystal structure; bioactivity 目前临床常用的细胞毒抗肿瘤药物选择性差、 癌等表皮细胞肿瘤中可见到 HER2 过度表达。人表皮 毒副作用大, 导致肿瘤疾病化学治疗的治疗指数不 生长因子受体 2 HER2 具有转化细