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  

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

作　　者：戎瑞雪[1,2] 李基民 李耀文 郭啸宇 王冲 李艳军[3] 李金梅[4] 韩宝君[3] 曹志然[1] 王克让[2] 李小六[2] Ruixue Rong;Jimin Li;Yaowen Li;Xiaoyu Guo;Chong Wang;Yanjun Li;Jinmei Li;Baojun Han;Zhiran Cao;Kerang Wang;Xiaoliu Li(College of Basic Medicine,Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province,Hebei University,Baoding,Hebei 071000;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;Forth Department of Orthopedic,Baoding First Central Hospital,Baoding,Hebei 071000;Department of Pathology,Baoding First Central Hospital,Baoding,Hebei 071000)

机构地区：[1]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 [2]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 [3]保定市第一中心医院骨四科,河北保定071000 [4]保定市第一中心医院病理科,河北保定071000

出　　处：《有机化学》2021年第4期1599-1606,共8页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(Nos.21572044,21778013);河北省自然科学基金(No.B2017201193);河北省卫生健康委员会基金(No.20202217);大学生创新项目(Nos.201910075009,2020338);河北大学高层次人才科研启动基金(No.521000981311)资助项目。

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10^(4)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.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 10^(4)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.

关 键 词：萘酰亚胺 细胞核 手性 细胞周期 

分 类 号：R914.5[医药卫生—药物化学] O657.3[医药卫生—药学]