新型樟脑磺胺基肟醚衍生物的合成及抗肿瘤活性研究  

Synthesis of Novel Camphor Sulfamoxime Ether Derivatives and Its Application in Antitumor Activity

作　　者：赵雨珣 王芸芸[1] 张成龙 徐徐[1] 王石发[1] Yuxun Zhao;Yunyun Wang;Chenglong Zhang;Xu Xu;Shifa Wang(Co-Innovation Center of Efficient Processing and Utilization of Forest Resources,College of Chemical Engineering,Nanjing Forestry University,Nanjing 210037)

机构地区：[1]南京林业大学林业资源高效加工利用协同创新中心化学工程学院,南京210037

出　　处：《有机化学》2021年第3期1224-1233,共10页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.32071707)资助项目。

摘　　要：利用药物设计中的活性拼接原理,以(+)-10-樟脑磺酸为原料,经酰氯化、酰胺化和缩合反应,设计合成了一系列樟脑磺胺基肟醚类衍生物,通过1HNMR、13CNMR和HRMS对其结构进行了表征.采用噻唑蓝(MTT)法对目标化合物对人肺腺癌细胞(A549)、人宫颈癌细胞(Hela)、人乳腺癌细胞(MCF-7)和人正常胚胎肝细胞(LO2)进行抗肿瘤活性评价。结果表明,大部分化合物显示出良好的抗肿瘤活性。其中,(+)-1-(7,7-二甲基-2-(苄氧基亚氨基)双环[2.2.1]庚烷-1-基)-N-(3-(三氟甲基)苯基)甲磺酰胺(4r)对三种细胞表现出最好的抗增值效果,IC50值分别为6.75、7.93和4.51μmol·L^(-1).采用流式细胞术检测细胞周期和凋亡,Hoechst染色观察细胞形态变化.荧光探针DCFH-DA和JC-1分别用于检测细胞内活性氧水平和线粒体膜电位.初步机理研究表明,化合物4r可将MCF-7细胞阻滞在G0/G1期,可诱导活性氧产生和线粒体膜电位崩溃进而诱导细胞呈剂量依赖式凋亡.Based on the combination principle in drug design,a series of camphor sulfamoxime ether derivatives were designed and synthesized with(+)-10-camphorsulfonic acid as the staring materials via acyl chlorination,acyl amidation and condensation.The target compounds were characterized by 1H NMR,13C NMR and HRMS spectra.In addition,the antiproliferative effects of compounds were evaluated on a panel of human adherent cell lines(A549,Hela,MCF-7 and LO2)by means of methyl thiazolyl tetrazolium(MTT)assays.Noticeably,(+)-1-(2-((benzyloxy)imino)-7,7-dimethylbicyclo[2.2.1]-heptan-1-yl)-N-(3-(trifluoromethyl)phenyl)me thanesulfonamide(4 r)possessed excellent antiproliferative against A549(6.75μmol·L-1),Hela(7.93μmol·L-1)and MCF-7(4.51μmol·L^(-1)).Flow cytometry was used to detect cell cycle progression and apoptosis,and morphological change of apoptosis was observed by Hoechst 33258 staining.Levels of reactive oxygen specy(ROS)and mitochondrial membrane potential were measured by DCFH-DA and JC-1,respectively.These results indicated that compound 4 r could cause cell cycle arrest at G0/G1 phase and triggered apoptosis in MCF-7 cells.Furthermore,4 r could induce the accumulation of ROS and mitochondrial disruption.Taken together,compound 4 r could be a potential anticancer drug candidate.

关 键 词：樟脑磺胺基肟醚 抗肿瘤活性 G0/G1期阻滞 凋亡 

分 类 号：TQ463[化学工程—制药化工]