去氢枞酸硝酸酯类化合物的合成及细胞毒性评价  

Synthesis and Cytotoxicity Evaluation of Dehydroabietic Acid Derivatives Bearing Nitrate Moiety

作　　者：李芳耀[1,2] 黄琳[2] 周小群 李倩 马献力[2] 段文贵[1] 王秀 Li Fangyao;Huang Lin;Zhou Xiaoqun;Li Qian;Ma Xianli;Duan Wengui;Wang Xiu(School of Chemistry and Chemical Engineering,Guangxi University,Nanning 530004;School of Pharmacy,Guilin Medical University,Guilin,Guangxi 541004)

机构地区：[1]广西大学化学化工学院,南宁530004 [2]桂林医学院药学院,广西桂林541004

出　　处：《有机化学》2020年第9期2845-2854,共10页Chinese Journal of Organic Chemistry

基　　金：广西自然科学基金(Nos.2018GXNSFAA138165,2018GXNSFAA281200);省部共建药用资源化学与药物分子工程国家重点实验室资助课题(广西师范大学)(No.CMEMR2019-B02);广西林产化学与工程重点实验室开放基金课题(No.GXFC18-02);广西农产资源化学与生物技术重点实验室开放基金(No.2019KF06);广西高等学校千名中青年骨干教师培育计划、广西高校中青年科研基础能力提升项目(No.2019KY051);桂林医学院中青年教职工科研基础能力提升(No.2018glmcy015)资助项目.

摘　　要：为寻找高效的抗肿瘤活性化合物,设计并合成了一系列新型的去氢枞酸硝酸酯类化合物.采用噻唑蓝(MTT)法测定目标化合物对鼻咽癌(CNE-2)、肝癌(HepG2,BEL-7402)和宫颈癌(He La)细胞株以及人正常肝细胞株(HL-7702)和鼻咽上皮细胞株(NP69)的细胞毒活性.结果表明,大多数杂合物的细胞毒性明显高于母体化合物.其中,12-溴去氢枞酸-3’-硝氧基丙酯(5j)对鼻咽癌CNE-2细胞株的抑制增殖活性优于顺铂,IC50值为(8.36±0.14)μmol/L,12,14-二硝基去氢枞酸-3’-硝氧基丙酯(5n)对肝癌BEL-7402细胞株的IC50值为(11.23±0.21)μmol/L.同时,目标化合物对人正常肝细胞株(HL-7702)和鼻咽上皮细胞株(NP69)表现出较低的细胞毒性.此外,对所有硝酸酯的NO释放量的测试表明,在大多数情况下,细胞毒性与CNE-2细胞株细胞内NO的释放水平呈正相关.In order to find more effective antitumor agents,a series of novel dehydroabietic acid derivatives bearing nitrate moiety were designed and synthesized.Their cytotoxicities were evaluated against human cancer cell lines of CNE-2(nasopharynx),HepG2(liver),HeLa(epithelial cervical)and BEL-7402(liver),and human normal liver cell(HL-7702)and nasopharyngeal epithelial cell(NP69)using methyl thiazolyl tetrazolium(MTT)assay.Biological screening results demonstrated that most of the hybrids exhibited more potent cytotoxicity superior to parent compound dehydroabietic acid.Among them,12-bromodehydroabietic acid-3’-nitrooxypropyl ester(5 j)displayed better antiproliferative activity with IC50 value of(8.36±0.14)μmol/L toward CNE-2 cells compared with cisplatin,and 2,14-dinitrodehydroabietic acid-3′-nitrooxypropyl ester(5 n)showed remarkable cytotoxicity with IC50 value of(11.23±0.21)μmol/L against BEL-7402 cells.Moreover,they exhibited lower cytotoxicity against human normal liver cell line HL-7702 and nasopharyngeal epithelial cell NP69.Besides,NO released amounts detection of all nitrates suggested that in most cases,the cytotoxicities were positively correlated with the levels of intracellular NO release in CNE-2 cells.

关 键 词：去氢枞酸 硝酸酯 合成 细胞毒性 

分 类 号：O623.624[理学—有机化学] TQ460.1[理学—化学]