去氢枞醇杂环类化合物的合成及细胞毒性研究  

Synthesis and cytotoxicity of dehydroabietinol derivatives bearing heterocycle

作　　者：孙金川 蔡隆强 朱明君 林飞宏 陶兰娟 吴宇媚 蒋彩娜[1] 李芳耀[1] SUN Jin-chuan;CAI Long-qiang;ZHU Ming-jun;LIN Fei-hong;TAO Lan-juan;WU Yu-mei;JIANG Cai-na;LI Fang-yao(School of Pharmacy,Guilin Medical University,Guilin 541004,China)

机构地区：[1]桂林医学院药学院,广西桂林541004

出　　处：《化学研究与应用》2022年第2期357-365,共9页Chemical Research and Application

基　　金：广西自然科学基金项目(2018GXNSFAA281200,2019GXNSFAA245035)资助;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)项目(CMEMR2019-B02)资助;广西脑与认知神经科学重点实验室开放课题项目(GKLBCN-20200108-03)资助;广西西高等学校千名中青年骨干教师培育计划项目资助;桂林医学院硕士研究生科研项目(GYYK2021010)资助。

摘　　要：以去氢枞酸(1)为原料,经氢化铝锂还原得到去氢枞醇(2),2与氯乙酰氯在氮气保护和DMAP催化条件下反应合成中间产物去氢枞醇氯乙酸酯(3),3与杂环化合物经亲核取代反应合成了12个新型去氢枞醇杂环类化合物(4a~4l)。利用IR、^(1)H NMR、^(13)C NMR和HR-MS等对目标化合物的结构进行表征,采用MTT法测试目标化合物对人肝癌细胞HepG2、人胃癌细胞MGC803、人膀胱癌细胞T24、人肺癌细胞A549和人正常肝细胞LO2等5种细胞株的体外细胞毒性。结果表明部分化合物对癌细胞表现出一定的细胞毒性,其中化合物4e和4j对MGC803细胞毒性较强,其IC_(50)值分别为1.28±0.68μM和3.93±1.22μM,4b和4j对T24细胞毒性较强,其IC_(50)值分别为3.66±0.72μM和3.74±0.38μM。值得注意的是化合物4j对MGC803和T24两种细胞株的细胞毒性与阳性药阿霉素相当,且对人正常肝细胞毒性较弱,具有进一步研究的价值。Dehydroabietinol(2)was synthesized from dehydroabietic acid(1)by the reduction of lithium aluminum hydride.Under the protection of nitrogen and DMAP as catalyst,dehydroabietinol reacted with chloroacetyl chloride to obtain the intermediate dehydroabietinol chloroacetate(3).Twelve new dehydroabietinol heterocyclic derivatives(4a~4l)were prepared by the nucleophilic substitution reaction of 3 with heterocyclic compounds.Their structures were characterized by IR,1H NMR,13C NMR and HR-MS,and cytotoxicities were evaluated against human liver cancer cell line HepG2,human gastric cancer cell line MGC803,human bladder cancer cell line T24,human lung cancer cell line A549 and human normal liver cell line LO2 by MTT assay in vitro.The results demonstrated that some of the hybrids exhibited potent cytotoxicity against the tested cells.Among them,4e and 4j exhibited promising cytotoxicity against MGC803 cells with IC_(50) value of 1.28±0.68μM and 3.93±1.22μM,respectively;4b and 4j displayed significant growth inhibitory activity against T24 cells with IC_(50) values of 3.66±0.72μM and 3.74±0.38μM,respectively.Compound 4j exhibited comparable inhibitory activity against MGC803 and T24 cells with doxorubicin and less toxicity to LO2,which was worthy of further investigation.

关 键 词：去氢枞酸 去氢枞醇 杂环化合物 细胞毒性 

分 类 号：O626[理学—有机化学]