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2021 , Vol. 41 >Issue 4: 1599 - 1606

DOI: https://doi.org/10.6023/cjoc202008015

研究论文

细胞核定位的萘酰亚胺类衍生物的合成及抗肿瘤作用研究

  • 戎瑞雪 ,
  • 李基民 ,
  • 李耀文 ,
  • 郭啸宇 ,
  • 王冲 ,
  • 李艳军 ,
  • 李金梅 ,
  • 韩宝君 ,
  • 曹志然 ,
  • 王克让 ,
  • 李小六
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  • a 河北大学基础医学院 河北省炎性自身免疫性疾病发病机制及防治重点实验室 河北保定 071000
    b 河北大学化学与环境科学学院 药物化学与分子诊断教育部重点实验室 河北省化学生物学重点实验室 河北保定 071002
    c 保定市第一中心医院骨四科 河北保定 071000
    d 保定市第一中心医院病理科 河北保定 071000

收稿日期: 2020-08-11

  修回日期: 2020-09-15

  网络出版日期: 2020-12-31

基金资助

国家自然科学基金(21572044); 国家自然科学基金(21778013); 河北省自然科学基金(B2017201193); 河北省卫生健康委员会基金(20202217); 大学生创新项目(201910075009); 大学生创新项目(2020338); 河北大学高层次人才科研启动基金(521000981311)

收起

Synthesis and Anti-tumor Effects of Naphthalimide Derivatives Targeted in Cell Nucleus

  • Ruixue Rong ,
  • Jimin Li ,
  • Yaowen Li ,
  • Xiaoyu Guo ,
  • Chong Wang ,
  • Yanjun Li ,
  • Jinmei Li ,
  • Baojun Han ,
  • Zhiran Cao ,
  • Kerang Wang ,
  • Xiaoliu Li
Expand
  • a College of Basic Medicine, Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Hebei University, Baoding, Hebei 071000
    b College of Chemistry and Environmental Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis (Ministry of Education), Key Laboratory of Chemical Biology of Hebei Province, Hebei University, Baoding, Hebei 071002
    c Forth Department of Orthopedic, Baoding First Central Hospital, Baoding, Hebei 071000
    d Department of Pathology, Baoding First Central Hospital, Baoding, Hebei 071000
* Corresponding authors. E-mail: ;
E-mail:

Received date: 2020-08-11

  Revised date: 2020-09-15

  Online published: 2020-12-31

Supported by

National Natural Science Foundation of China(21572044); National Natural Science Foundation of China(21778013); Natural Science Foundation of Hebei Province(B2017201193); Foundation of Health Commission of Hebei Province(20202217); Innovation Project of Students(201910075009); Innovation Project of Students(2020338); Hebei University High-level Talent Research Startup Project(521000981311)

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摘要

以4-溴-1,8-萘酐为原料, 经亲核取代反应合成了系列手性氨基醇修饰的萘酰亚胺衍生物NI1~NI8. 四甲基偶氮唑蓝(MTT)法研究了其细胞毒性, 发现含有伯羟基氨基醇修饰的萘酰亚胺衍生物中R型的细胞毒性好于S型异构体. 经紫外光谱、荧光光谱和激光共聚焦实验研究了化合物(R)-2-(2-(二甲基氨基)乙基)-6-((1-羟基-2-丙烷基)氨基)-萘酰亚胺(NI1)和(S)-2-(2-(二甲基氨基)乙基)-6-((1-羟基-2-丙烷基)氨基)-萘酰亚胺(NI2)与DNA分子和HeLa细胞的相互作用, 发现其能有效与脱氧核糖核酸(DNA)络合, 键合常数达到104 L?mol–1; 且NI1和NI2与HeLa细胞作用可定位于细胞核. 流式细胞实验结果显示NI1和NI2能够使细胞周期阻滞于S期而抑制细胞增殖. 小鼠体内血液毒性结果显示NI1对血液中的红细胞、白细胞和血小板无明显影响.

关键词： 萘酰亚胺; 细胞核; 手性; 细胞周期

本文引用格式

戎瑞雪 , 李基民 , 李耀文 , 郭啸宇 , 王冲 , 李艳军 , 李金梅 , 韩宝君 , 曹志然 , 王克让 , 李小六 . 细胞核定位的萘酰亚胺类衍生物的合成及抗肿瘤作用研究[J]. 有机化学, 2021 , 41(4) : 1599 -1606 . DOI: 10.6023/cjoc202008015

Abstract

A series of novel chiral amino alcohol modified naphthalimide derivatives NI1~NI8 were designed and synthesized by nucleophilic substitution reaction. Furthermore, their cytotoxicities were studied by thiazolyl blue tetrazolium bromide (MTT) method. The cytotoxicity of the R-type isomer in the naphthalimide derivatives with primary hydroxyl amino alcohol modification was better than that of the S-type isomer. In addition, deoxyribonucleic acid (DNA) binding interactions and fluorescence imaging of (R)-2-(2-(dimethylamino)ethyl)-6-((1-hydroxypropan-2-yl)amino)-naphthalimide (NI1) and (S)-2-(2-(dimethylamino)ethyl)-6-((1-hydroxypropan-2-yl)amino)-naphthalimid (NI2) with Ct-DNA and HeLa cells were investigated. NI1 and NI2 showed strong binding interactions with Ct-DNA with a bonding constant of 104 L/mol. And NI1 and NI2 exhibited nucleus-targeting imaging for HeLa cells. NI1 and NI2 mainly arrested the S phase. Moreover, the hematoxic results of NI1in mice showed no significant effects on the red blood cells, white blood cells and platelets in the blood.

Key words： naphthalimide; nucleus; chiral; cell cycle

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