β-咔啉杂合咪唑类化合物的合成及体外抗肿瘤活性  

Synthesis and in vitro antitumor activity ofβ-carboline hybrid imidazole derivatives

作　　者：陈亮 郭亮 肖艳博 马芹 陈伟 张洁[1] CHEN Liang;GUO Liang;XIAO Yanbo;MA Qin;CHEN Wei;ZHANG Jie(Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan,School of Chemistry and Chemical Engineering,Shihezi University,Shihezi 832003,Xinjiang,China;Xinjiang Huashidan Pharmaceutical Research Co.,Ltd.,Urumqi 830011,Xinjiang,China)

机构地区：[1]石河子大学化学化工学院新疆兵团化工绿色过程重点实验室,新疆石河子832003 [2]新疆华世丹药物研究有限责任公司,新疆乌鲁木齐830011

出　　处：《精细化工》2024年第4期881-889,共9页Fine Chemicals

基　　金：国家自然科学基金项目(22067017);兵团指导性计划项目(2022ZD019);兵团第二师科技重大专项(2021SFGG01)。

摘　　要：以L-色氨酸为原料,经Pictet-Spengler环化反应、氧化脱羧、N^(9)-烷基化等反应步骤,合成了一系列β-咔啉杂合咪唑类化合物。目标化合物经1HNMR、13CNMR和HRMS确证结构。采用MTT(噻唑蓝)法检测了目标化合物对肺癌细胞(A-549)、胃癌细胞(BGC-823)、结肠癌细胞(CT-26)、肝癌细胞(Bel-7402)和乳腺癌细胞(MCF-7)的体外抗肿瘤活性。结果表明,大部分化合物对这5种肿瘤细胞株表现出了中等及优良的抑制活性。特别是3-苄基-11-(3-苯基丙基)-11H-咪唑并[1',5':1,2]吡啶并[3,4-b]吲哚(Ⅴr)对CT-26、Bel-7402和MCF-7细胞株的体外抗肿瘤活性较高,对应的半数抑制浓度(IC_(50))分别为(9.5±0.4)、(7.4±0.3)和(8.8±0.6)µmol/L。分子对接结果表明,3-苄基-11-甲基-11H-咪唑并[1',5':1,2]吡啶并[3,4-b]吲哚(Ⅴa)、3-苄基-11-丁基-11H-咪唑并[1',5':1,2]吡啶并[3,4-b]吲哚(Ⅴf)和Ⅴr与VEGFR^(2)激酶的多个氨基酸残基具有良好的结合作用。A series ofβ-carboline hybrid imidazole compounds were synthesized from L-tryptophan by Pictet-Spengler cyclization,oxidative decarboxylation and N9-alkylation,and then characterized by 1HNMR,13CNMR and HRMS.The in vitro antitumor activities ofβ-carboline hybrid imidazole derivatives against five cancer cell lines of lung cancer cells(A-549),stomach cancer cells(BGC-823),colon cancer cells(CT-26),liver cancer cells(Bel-7402),and breast cancer cells(MCF-7)were evaluated using thiazolylblue(MTT)method.The results showed that most of the compounds exhibited moderate to excellent activity against the tested cancer cell lines.Especially,3-benzyl-11-(3-phenylpropyl)-11H-imidazo[1',5':1,2]pyrido[3,4-b]indole(Ⅴr)showed the most potent anti-proliferative activity against CT-26,Bel-7402,and MCF-7 cell lines with corresponding median inhibitory concentration(IC_(50))of(9.5±0.4),(7.4±0.3),and(8.8±0.6)µmol/L,respectively.Molecular docking results revealed that 3-benzyl-11-methyl-11H-imidazo[1',5':1,2]pyrido[3,4-b]indole(Ⅴa),3-benzyl-11-butyl-11H-imidazo[1',5':1,2]pyrido[3,4-b]indole(Ⅴf),andⅤr had a good binding effect on several amino acid residues of VEGFR^(2) enzyme.

关 键 词：β-咔啉杂合咪唑 合成 抗肿瘤 构效关系 分子对接 医药原料 

分 类 号：O626[理学—有机化学] R979.1[理学—化学]