[1]周瑾,廖柏鸿,邓颖归,等.咪唑并杂环化合物的设计、合成及抗乳腺癌活性评价[J].南方医科大学学报,2018,(09):1052.[doi:10.12122/j.issn.1673-4254.2018.09.05]
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咪唑并杂环化合物的设计、合成及抗乳腺癌活性评价()
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《南方医科大学学报》[ISSN:1673-4254/CN:44-1627/R]

卷:
期数:
2018年09期
页码:
1052
栏目:
出版日期:
2018-09-30

文章信息/Info

Title:
Design and synthesis of imidazo-fused heterocycles derivatives and their anti-tumor activity against breast cancer in mice
作者:
周瑾廖柏鸿邓颖归郭小文赵嘉兰孙杰朱志博
关键词:
咪唑杂环抗癌凋亡乳腺癌
Keywords:
imidazole heterocycle anti-cancer apoptosis breast cancer
DOI:
10.12122/j.issn.1673-4254.2018.09.05
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Buchwald- Hartwig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,IC50值是9.77±2.32 μmol/L,接近阳性对照药物顺铂(IC50=8.96±2.35 μmol/L),且肾毒性略小于顺铂(2a 的CC50为 10.79±0.87 μmol/L,顺铂的CC50为8.45±0.68 μmol/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。
Abstract:
Objective To synthesize compounds based on imidazo-fused heterocycles and evaluate their anti-tumor activity against breast cancer. Methods The compounds 1a-1e, 2a and 2b were synthesized by aerobic copper-catalyzed halocyclization of methyl N-heteroaromatics with aliphatic amines; 3a and 3b were generated by sonogashira reaction and Suzuki reaction, respectively; the compounds 4a-4c were obtained by Buchwald-Hartwig reaction of the corresponding amines and 1e. 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 2a (daily dose of 10 mg/kg for 14 days) was tested in a mouse model bearing human breast cancer xenografts. Results The compounds 2a, 4a, 4b and 4c all showed obvious anti-tumor activities. Among these compounds, 2a showed the most potent anti-tumor effect against breast cancer cells with an IC50 of 9.77 ± 2.32 μmol/L, similar to that of cisplatin (IC50=8.96 ± 2.35 μmol/L); 2a also showed a slightly lower nephrotoxicity than cisplatin, and their CC50 was 10.79±0.87 μmol/L and 8.45±0.68 μmol/L, respectively. 2a 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 2a 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.
更新日期/Last Update: 1900-01-01