摘要
目的合成以咪唑并杂环为母体的化合物,并评价抗乳腺癌活性。方法利用甲基N-杂环化合物与脂肪胺的有氧铜催化的卤环化反应合成1a-1e、2a和2b;通过sonogashira偶联反应合成3a;使用suzuki偶联反应合成3b;相应胺与1e的BuchwaldHartwig偶联分别得到4a-4c。通过MTT法测定目标化合物的抗乳腺癌活性和肾毒性。通过Annexin V-FITC/PI试剂盒检测目标化合物对乳腺癌细胞的凋亡诱导作用。通过裸鼠异种移植模型评价2a的体内安全性和有效性:利用SPSS产生随机数字将裸鼠随机分为治疗组与对照组,每组6只。治疗组腹腔注射2a的生理盐水溶液[10 mg/(kg·d)];对照组注射等量生理盐水,持续14 d。实验结束时处死小鼠,取出肿瘤并测量,计算体积。结果通过活性筛选发现4个活性较好的化合物2a、4a、4b和4c。其中2a活性最好,IC_(50)值是9.77±2.32μmol/L,接近阳性对照药物顺铂(IC_(50)=8.96±2.35μmol/L),且肾毒性略小于顺铂(2a的CC_(50)为10.79±0.87μmol/L,顺铂的CC_(50)为8.45±0.68μmol/L)。2a促进乳腺癌细胞发生凋亡。2a在10 mg/(kg·d)的剂量下对小鼠体内肿瘤生长有一定抑制作用,且未引起严重不良反应。结论合成了12个咪唑并杂环化合物,有3个结构新颖的化合物。发现4个抗癌活性较好的化合物。化合物2a以浓度依赖的方式促进sk-br-3细胞凋亡,从而引起细胞死亡。2a在体内具有安全性和一定的抗乳腺癌活性。
Objective To synthesize compounds based on imidazo-fused heterocycles and evaluate their anti-tumor activity against breast cancer. Methods The compounds 1 a-1 e, 2 a and 2 b were synthesized by aerobic copper-catalyzed halocyclization of methyl N-heteroaromatics with aliphatic amines; 3 a and 3 b were generated by sonogashira reaction and Suzuki reaction,respectively; the compounds 4 a-4 c were obtained by Buchwald-Hartwig reaction of the corresponding amines and 1 e. The effects of these compounds against breast cancer cells and their nephrotoxicity were determined using MTT assay. Annexin VFITC/PI apoptosis detection kit was used to assess the apoptosis-inducing effects of these compounds in breast cancer cells.With normal saline as the control, the safety and anti-tumor activity of the compound 2 a（daily dose of 10 mg/kg for 14 days）was tested in a mouse model bearing human breast cancer xenografts. Results The compounds 2 a, 4 a, 4 b and 4 c all showed obvious anti-tumor activities. Among these compounds, 2 a showed the most potent anti-tumor effect against breast cancer cells with an IC_（50） of 9.77 ± 2.32 μmol/L, similar to that of cisplatin（IC_（50）=8.96 ± 2.35 μmol/L）; 2 a also showed a slightly lower nephrotoxicity than cisplatin, and their CC_（50） was 10.79±0.87 μmol/L and 8.45±0.68 μmol/L, respectively. 2 a obviously promoted apoptosis of breast cancer cells in vitro and caused a moderate suppression of the breast cancer growth in the tumor-bearing mouse models without producing serious adverse effects. Conclusion Four compounds synthesized based on imidazo-fused heterocycles have anti-tumor activities against breast cancer. The compound 2 a is capable of dose-dependently promoting apoptosis of breast cancer cells in vitro and has a good safety and a moderate efficacy for suppressing tumor growth in mouse models bearing human breast cancer xenografts.
作者
周瑾
廖柏鸿
邓颖归
郭小文
赵嘉兰
孙杰
朱志博
ZHOU Jin;LIAO Bohong;DENG Yinggui;ZHAO Jialan;SUN Jie;ZHU Zhibo(Department of Nursing,2.Clinical Research Center,Integrated Hospital of Traditional Chinese Medicine,Southern Medical University,Guangzhou 510315,China)
出处
《南方医科大学学报》
CAS
CSCD
北大核心
2018年第9期1052-1060,共9页
Journal of Southern Medical University
基金
国家自然科学基金(81373263)
广东省科技计划项目(粤科规财字[2015]110号)~~
关键词
咪唑
杂环
抗癌
凋亡
乳腺癌
vimidazole
heterocycle
anti-cancer
apoptosis
breast cancer
