新型苯并吗啉-8-甲酰胺衍生物的合成及抗肿瘤活性  

Synthesis and Antitumor Activities of Novel Benzomorpholinyl-8-formamide Derivatives

作　　者：奉强 常波 何华龙 雷侠 李倩意 朱建豪 燕艳 余洛汀[2] 张小玲 FENG Qiang;CHANG Bo;HE Hua-long;LEI Xia;LI Qian-yi;ZHU Jian-hao;YAN Yan;YU Luo-ting;ZHANG Xiao-ling(Colledge of Chemistry and Life Science,Sichuan Provincial Key Laboratory for Structural Optimization and Application of Functional Molecules,Chengdu Normal University,Chengdu 611130,China;State Key Laboratory of Biotherapy,Sichuan University,Chengdu 610041,China)

机构地区：[1]成都师范学院化学与生命科学学院功能分子结构优化与应用四川省高校重点实验室,四川成都611130 [2]四川大学生物治疗国家重点实验室,四川成都610041

出　　处：《合成化学》2021年第10期822-829,共8页Chinese Journal of Synthetic Chemistry

基　　金：四川省科技厅应用基础研究项目(2020YFS0311)。

摘　　要：以6-溴N-(4,6-二甲基-2-氧代-1,2-二氢吡啶-3-甲基)苯并吗啉-8-甲酰胺为原料,经N-磺酰化和Suzuki偶联反应两步合成17个新型的6-芳基取代N-磺酰基苯并吗啉-8-甲酰胺衍生物(3a~3q),其结构经1 H NMR、13 C NMR和MS(EI)表征。采用Alpha LISA法对化合物进行EZH2(WT)酶活性检测;采用MTT法测试了化合物对非小细胞肺癌细胞A549和人类B细胞淋巴瘤细胞SU-DHL-4的细胞增殖抑制作用。结果表明:化合物3j的浓度为1μmol·L^(-1)时,对EZH2抑制率为68%;对A549细胞和SU-DHL-4细胞的IC 50值分别达到10.4μmol·L^(-1)和2.8μmol·L^(-1)。Seventeen novel 6-aryl substituted N-sulfonyl benzomorpholinyl-8-formamide derivatives were synthesized as Enhancer of Zeste Homolog 2(EZH2)inhibitors(3a~3q)by N-sulfonylation and Suzuki coupling reaction using 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-2 H-benzo[b][1,4]oxazine-8-carboxamide as starting material.The structures were characterized by ^(1)H NMR,^(13)C NMR and MS(EI).In vitro enzyme activities of the compounds were detected by Alpha LISA screening method and the inhibition of the compounds on the proliferation of A549 and human B-cell lymphoma cell SU-DHL-4 have been demonstrated by MTT assays.The results showed that the strongest inhibitory activity against EZH2 enzyme,A549 and SU-DHL-4 cell lines was compound 3j(IC_(50)=10.4 and 2.8μmol·L^(-1)).

关 键 词：苯并吗啉-8-甲酰胺 EZH2抑制剂 抗肿瘤活性 合成 N-磺酰化 偶联 酶活性 

分 类 号：O621.3[理学—有机化学] O625[理学—化学]