含磺酰胺基团氨基甲酸去氢枞醇酯衍生物的合成及体外抗肿瘤活性  

Synthesis and in vitro antitumor activity of sulfonamide-substituted dehydroabietyl carbamate derivatives

作　　者：王德荣 庞富华 钱威 李芳耀[1] WANG Derong;PANG Fuhua;QIAN Wei;LI Fangyao(Guangxi Key Laboratory of Drug Discovery and Optimization,Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation,Key Laboratory of Medical Biotechnology and Translational Medicine,School of Pharmacy,Guilin Medical University,Guilin 541199,Guangxi,China)

机构地区：[1]桂林医学院药学院、广西药物分子发现与成药性优化重点实验室、广西药物分子筛选与成药性评价工程研究中心、广西高校医药生物技术与转化医学重点实验室,广西桂林541199

出　　处：《精细化工》2024年第11期2493-2503,共11页Fine Chemicals

基　　金：广西自然科学基金项目(2023GXNSFAA026277);桂林市科学研究与技术开发计划项目(20210227-1);广西林产化学与工程重点实验室开放课题资助项目(GXFK2202);广西药物分子发现与成药性优化重点实验室课题(GKLPMDDO-2022-P02);广西高等学校千名中青年骨干教师培育计划资助项目;桂林医学院硕士研究生科研项目(GYYK2023017);国家级大学生创新创业训练计划项目(202310601037)。

摘　　要：去氢枞酸经还原、酯化和氨基化3步反应合成了19个N-(氨基磺酰基)氨基甲酸去氢枞醇酯类化合物(Ⅳa~Ⅳs),经FTIR、^(1)HNMR、^(13)CNMR和ESI-MS对其结构进行了确认。以5-氟尿嘧啶(5-FU)为阳性对照,采用四甲基偶氮唑盐比色法评价了Ⅳa~Ⅳs对T-24、HepG2、MCF-7、MGC-803和Hela 5种肿瘤细胞株的体外抗肿瘤活性。利用Hoechst-33258染色、细胞集落形成、细胞周期分布、细胞凋亡和蛋白质印迹实验探究了N-[(2-溴苯基)氨基磺酰基]氨基甲酸去氢枞醇酯(Ⅳd)初步作用机制。结果表明,部分化合物抗肿瘤活性优于5-FU,其中,化合物Ⅳd对T-24细胞的细胞毒性活性最好,其半抑制浓度为(14.64±0.46)μmol/L,可明显抑制T-24细胞的生长,阻滞其细胞周期于S期(即DNA合成期);Ⅳd通过线粒体介导的内源性Caspase途径,下调抗凋亡蛋白Bcl-2、Caspase3、Caspase9的表达水平,上调促凋亡蛋白Bax、Cleaved Caspase9、Cleaved Caspase9的表达水平,从而诱导和促进T-24发生凋亡。磺酰胺结构的引入能够改善去氢枞酸衍生物的抗肿瘤活性。Nineteen kinds of N-(aminosulfonyl)dehydrofirnyl carbamate compounds were synthesized from dehydroabietic acid via reduction,esterification and amination three step reaction,and characterized by FTIR,^(1)HNMR,^(13)CNMR,and ESI-MS.The antitumor activity ofⅣa~Ⅳs against T-24,HepG2,MCF-7,MGC-803 and Hela tumor cell lines was evaluated using 5-fluorouracil as positive control by tetramethylazolium salt colorimetric assay,followed by analysis on the preliminary mechanism of N-[(2-bromophenyl)sulfamyl]dehydrofirnyl carbamate(Ⅳd)via Hoechst-33258 staining,cell colony formation,cell cycle distribution,cell apoptosis and western blot assay.The results showed that some compounds exhibited superior antitumor activity in comparison with positive drugs,with compoundⅣd displaying the best activity against T-24 cells with a half inhibitory concentration of(14.64±0.46)μmol/L,arresting the cell cycle in the S phase thus significantly inhibiting the growth of T-24 cells.In addition,compoundⅣd could promote T-24 cells apoptosis through upregulation of proapoptotic ones Bax,Cleaved Caspase9,Cleaved Caspase9 and downregulation of antiapoptotic protein Bcl-2,Caspase3,Caspase9 expression.The introduction of sulfanilamide structure could improve the anti-tumor activity of dehydroabietic acid derivatives.

关 键 词：去氢枞酸 去氢枞醇 氨基甲酸酯 抗肿瘤活性 凋亡 医药原料 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]