甾体结构新型细胞周期蛋白依赖激酶8抑制剂的合成及活性评价  

Synthesis and bioactivity evaluation of novel CDK8 inhibitors with steroid structure

作　　者：杨可扬 谢雨欣 宋雪琴 徐亮[1] YANG Keyang;XIE Yuxin;SONG Xueqin;XU Liang(Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology,Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry,West China School of Pharmacy,Sichuan University,Chengdu,Sichuan,610041P.R.China)

机构地区：[1]四川大学华西药学院,靶向药物与释药系统教育部和四川省重点实验室,四川省植物来源药物工程实验室四川省小分子药物精准化工程技术研究中心,四川成都610041

出　　处：《华西药学杂志》2024年第6期639-645,共7页West China Journal of Pharmaceutical Sciences

摘　　要：目的合成具有细胞周期蛋白依赖激酶8(CDK8)抑制活性结构新颖的甾体衍生物,为开发新型抗肿瘤药物提供先导化合物。方法以孕烯醇酮为起始物,通过关键的Sonogashira炔基偶联反应和胺基引入,分别对甾体C-17位和C-3位进行修饰,并针对激酶CDK8的半数抑制浓度(IC_(50))测试制备的化合物。结果制备了10个目标分子,其中化合物Ⅰe具有最强的激酶抑制活性(IC_(50)=18 nmol·L^(-1))。结论通过优化甾体结构,得到了具有强CDK8激酶抑制活性的新化合物,可为抗肿瘤药物开发提供参考。OBJECTIVE Steroid derivatives with novel structures and cyclin-dependent kinase 8(CDK8)inhibitory activity were synthesized to provide lead compounds for the development of novel anti-tumor drugs.METHODS Pregnenolone was used as the starting material,and the steroid C-17 and C-3 positions were modified by the key Sonogashira alkyne coupling reaction and amine group introduction,respectively.The prepared compounds were tested for IC_(50)of the CDK8 kinase.RESULTS Ten targeted molecules were synthesized,among which compoundⅠe exhibited the strongest kinase inhibitory activity(IC_(50)=18 nmol·L^(-1)).CONCLUSION By optimizing the structure of steroid,new compounds with potent CDK8 kinase inhibitory activity were obtained,which can provide reference for the development of anti-tumor drugs.

关 键 词：细胞周期蛋白依赖性激酶 肿瘤 甾体 合成 SONOGASHIRA反应 胺基化 细胞周期蛋白依赖激酶8 

分 类 号：R914[医药卫生—药物化学]