含氟3-羟基吲哚-2-酮衍生物的合成及抗癌活性  

Synthesis and Anticancer Activities of Fluorine-Containing 3-Hydroxy-Indolin-2-One Derivatives

作　　者：王京[1] 郑诚月 刘来[1] 张磊[1] 史大斌[1] 姚其正[2] WANG Jing;ZHENG Cheng-yue;LIU Lai;ZHANG Lei;SHI Da-bin;YAO Qi-zheng(School of Pharmacy, Zunyi Medical University, Zunyi 563003, Guizhou, China;School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China)

机构地区：[1]遵义医学院药学院,贵州遵义563000 [2]中国药科大学药学院,江苏南京210009

出　　处：《精细化工》2018年第6期1022-1028,共7页Fine Chemicals

基　　金：贵州省科技厅基金项目([2014]7565,[2014]7557,[2017]1219);遵义医学院博士启动基金项目(F-631);遵义医学院扶持学科(药物化学)建设项目~~

摘　　要：通过Aldol缩合反应,在3-羟基吲哚-2-酮结构中引入不同的药效基团,设计并合成了含氟3-羟基吲哚-2-酮衍生物,其结构通过-1HNMR、-（13）CNMR和HRMS确证。目标产物对非小细胞肺癌A549细胞的体外抑制作用通过CCK-8法测定。结果显示,化合物Ⅲe和Ⅲf具有较强的抗肿瘤增殖活性,IC50分别为19.494和24.804μmol/L。流式细胞术和Hoechst 33342染色实验结果表明,化合物Ⅲe能够将A549细胞周期阻滞在G2期,并诱导细胞凋亡。此外,蛋白质免疫印迹法（Western blot）结果还显示,化合物Ⅲe能够上调蛋白P53和Cleaved Caspase-3的表达,并下调蛋白Survivin的表达。分子对接实验表明,化合物Ⅲe能够结合到磷脂酰肌醇3-激酶（PI3K-δ）的ATP口袋中。结果表明,化合物Ⅲe是具有潜在研究价值的抗非小细胞肺癌先导化合物。A series of fluorine-containing 3-hydroxy-indolin-2-one derivatives were designed and prepared by Aldol condensation reaction through the introduction of different pharmacophore structures into 3-hydroxy-indolin-2-one core scaffold. These compounds were confirmed by -1HNMR,-（13）CNMR and HRMS. And the antiproliferative activities of target molecules against non-small cell lung cancer A549 cells were evaluated by CCK-8 assay. The results showed that compounds Ⅲe and Ⅲf displayed stronger antiproliferative activities,with the IC50 values of 19.494 and 24.804 μmol/L,respectively. Flow cytometry and Hoechst 33342 staining demonstrated that compound Ⅲe could trigger cell cycle arrest at G2 phase and induce apoptosis of A549 cells. Moreover,Western blot indicated that compound Ⅲe could upregulate the levels of P53 and Cleaved Caspase-3,and downregulate the level of Survivin. Molecular docking simulation indicated that compound Ⅲe could bind to the ATP pocket of PI3 K-δ. Together,these data imply that compound Ⅲe maybe a potential candidate for the treatment of non-small cell lung cancer.

关 键 词：3-羟基吲哚-2-酮 含氟 衍生物 抗肿瘤活性 细胞周期 细胞凋亡 医药原料 

分 类 号：R914.4[医药卫生—药物化学]