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研究简报

5-氯-β-咔啉衍生物的合成、晶体结构与抗肿瘤活性

孙跃a, 郭亮a, 范文玺b, 陈伟b, 张洁a, 代斌a   

  1. a 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 石河子 832003;
    b 新疆华世丹药物研究有限责任公司 乌鲁木齐 830011
  • 收稿日期:2020-06-15 修回日期:2020-08-06 出版日期:2030-01-01 发布日期:2020-08-27
  • 通讯作者: 张洁, 代斌 E-mail:zhangjie-xj@163.com;db_tea@shzu.edu.cn
  • 基金资助:
    石河子大学科研计划(No.SHYL-YB201804),教育部长江学者和创新团队发展计划(No.IRT15R46),石河子大学长江学者研究项目(No.CJXZ201601)资助项目.

Synthesis, Crystal Structure and Antitumor Activity of Novel 5-Chloro-β-carboline Derivatives

Sun Yuea, Guo Lianga, Fan Wenxib, Chen Weib, Zhang Jiea, Dai Bina   

  1. a School of Chemistry and Chemical Engineering, Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi University, Shihezi, 832003;
    b Xinjiang Huashidan Pharmaceutical Research Co., Ltd., Urumqi, 830011
  • Received:2020-06-15 Revised:2020-08-06 Online:2030-01-01 Published:2020-08-27
  • Supported by:
    Project supported by the Scientific Research Innovation Project in Shihezi University (No. SHYL-YB201804), the Program for Changjiang Scholars and Innovative Research Team in University (No. IRT15R46), and Yangtze River Scholar Research Project of Shihezi University (No. CJXZ201601).

以1-甲基-β-咔啉为原料,经过硝化,N9-烷基化反应和还原胺化反应等步骤,最终合成得到一系列新型的5-氯-β-咔啉衍生物,目标化合物的结构经1H NMR,13C NMR以及HRMS确证。并利用单晶X射线衍射分析了化合物N-(吡啶-3-基)甲基-5-氯-1,9-二甲基-β-咔啉-6-胺(5e)的精确结构。采用噻唑蓝(MTT)法测试了目标化合物对肺癌细胞A549、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的细胞增殖抑制作用。实验结果表明部分化合物具有较好的抗肿瘤活性,特别化合物N-(2,6-二氟苄基)-1-甲基-5-氯-9-(2,3,4,5,6-五氟苄基)-β-咔啉-6-胺(5j)和N-(吡啶-3-基甲基)-1-甲基-5-氯-9-(2,3,4,5,6-五氟苄基)-β-咔啉-6-胺(5m)对所测试的4种肿瘤细胞株均有较高的抑制活性,其IC50值均小于10 μM.

关键词: 5-氯-β-咔啉, 合成, 抗肿瘤, 构效关系

Sixteen novel 5-chloro-β-carboline derivatives were synthesized from harmane in four steps:N9-alkylation, nitration, reduction, and Borch reduction. The structures of target compounds were confirmed by 1H NMR, 13C NMR, and HRMS. A single crystal of compound 5-chloro-1,9-dimethyl-N-(pyridin-3-ylmethyl)-β-carboline (5e) was cultured, and its single crystal structure was determined by X-ray diffraction study. The in vitro antiproliferative activities were evaluated in a panel of cancer cell lines (A549, BGC-823, CT-26, Bel-7402, and MCF-7) via methyl thiazolyl tetrazolium (MTT) assay. The results indicated that some of the compounds had good activities, and especially N-(2,6-difluorobenzyl)-1-methyl-5-chloro-9- (2,3,4,5,6-pentafluorobenzyl)-β-carboline-6-amine (5j) and N-(pyridin-3-ylmethyl)-1-methyl-5-chloro-9-(2,3,4,5,6-pentafluoro benzyl)-β-carboline-6-amine (5m) showed considerable antitumor activity, with IC50 values lower than 10 μM against four cancer cell lines.

Key words: 5-chloro-β-carboline, synthesis, antitumor, structure-activity relationship