济源冬凌草甲素衍生物作为潜在抗肿瘤药物的合成及药理学活性研究  

Study on Synthesis and Pharmacological Research of Jiyuan Oridonin A Derivatives as Potential Anti-tumor Drugs

作　　者：王妮 郑姿君 贾小苹 赵梦圆 王亚蕾 周臣 王志佳 肖泽霖 刘宏民 可钰 Wang Ni;Zheng Zijun;Jia Xiaoping;Zhao Mengyuan;Wang Yalei;Zhou Chen;Wang Zhijia;Xiao Zelin;Liu Hongmin;Ke Yu(Key Laboratory of Advanced Drug Preparation Technologies,Ministry of Education,School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001;State Key Laboratory of Esophageal Cancer Prevention&Treatment,Zhengzhou 450001;School of Health Sciences,Guangzhou Xinhua College,Guangzhou 510310)

机构地区：[1]郑州大学药物研究院药物关键制备技术教育部重点实验室,郑州450001 [2]省部共建食管癌防治国家重点实验室,郑州450001 [3]广州新华学院健康学院,广州510310

出　　处：《有机化学》2023年第2期646-659,共14页Chinese Journal of Organic Chemistry

基　　金：Project supported by the National Natural Sciences Foundations of China(No.U1904163);the Key Research Program of Henan Province(No.161100311000)。

摘　　要：济源冬凌草甲素(JOA)是从河南省济源市收集的冬凌草中纯化得到的二萜类成分,表现出多种抗肿瘤活性.为了进一步研究JOA的药用效果,设计合成了一系列其14-OH苯甲酸衍生物,随后评估了它们的体外抗增殖活性.结果证明,该系列衍生物的抗肿瘤活性优于先导化合物JOA及冬凌草甲素.其中,7α,20-内酯-对映-贝壳杉-16-烯-11,15二酮-14β-(2-硝基-5-氯苯甲酸)酯(OJW8-9)的活性最好[对SW1990细胞的IC_(50)=(0.478±0.109)μmol/L].进一步的作用机制研究表明,化合物OJW8-9通过阻断处于G2/M期的SW-1990来抑制细胞增殖,且具有浓度依赖性,其可能通过活性氧(ROS)途径诱导细胞凋亡.Jiyuan oridonin A(JOA),a diterpenoid ingredient purified from Isodon rubescens collected in Jiyuan,Henan Province,exhibited a variety of anti-tumor activities.In order to further develop the medicinal potency of JOA,a series of its 14-OH benzoate derivatives were designed and synthesized,and then their anti-proliferative activities in vitro were evaluated.The results turned out that the anti-tumor activities of this series of derivatives had been improved compared with the those of JOA,and were much better than that of oridonin.Among them,7α,20-olide-ent-kaur-16-en-11,15-dione-14β-yl 2-nitro-5-chlorobenzoate(OJW8-9)showed the best activity(IC_(50)=(0.478±0.109)μmol/L on SW-1990 cells).Further studies revealed that compound OJW8-9 inhibited the proliferation of SW-1990 cells by blocking cell cycle in the G2/M phase in a time-and concentration-dependent,and might induce apoptosis through reactive oxygen species(ROS)pathway.

关 键 词：对映-贝壳杉烯二萜 济源冬凌草甲素 抗增殖活性 活性氧 

分 类 号：TQ460.1[化学工程—制药化工]