有机化学 ›› 2016, Vol. 36 ›› Issue (1): 121-129.DOI: 10.6023/cjoc201507012 上一篇    下一篇

研究论文

色胺酮衍生物设计、合成及抗肿瘤活性构效关系研究

侯宝龙a, 艾芸a,b, 王翠玲a, 张宁a, 杨柳a, 刘竹兰a, 刘建利a   

  1. a 西部资源生物与现代生物技术省部共建教育部重点实验室 西北大学生命科学学院 西安 710069;
    b 西安市食品药品监督检验所 西安 710054
  • 收稿日期:2015-07-15 修回日期:2015-09-14 出版日期:2016-01-25 发布日期:2015-09-25
  • 通讯作者: 刘建利 E-mail:jlliu@nwu.edu.cn
  • 基金资助:

    陕西省自然科学基金(No. 2014JM4095)、陕西省教育厅基金(No. 12JK1010)和陕西省重点科技创新团队计划(No. 2013KCT-24)资助项目.

Design, Synthesis and Structure-Activity Relationship ofTryptanthrins as Antitumor Agents

Hou Baolonga, Ai Yuna,b, Wang Cuilinga, Zhang Ninga, Yang Liua, Liu Zhulana, Liu Jianlia   

  1. a Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069;
    b Xi'an Institute for Food and Drug Control, Xi'an 710054
  • Received:2015-07-15 Revised:2015-09-14 Online:2016-01-25 Published:2015-09-25
  • Supported by:

    Project supported by the Shaanxi Provincial Natural Science Fundation (No. 2014JM4095), the Foundation of the Education Department of Shaanxi Province (No. 12JK1010), the Key Program for Science and Technology Innovative Research Team of Shaanxi Province (No. 2013KCT-24).

首先合成吲哚醌衍生4a4f, 氧化水解得到邻氨基苯甲酸衍生物5a5d. 以这两者为原料设计合成A和/或D环取代的色胺酮衍生物1a1q. 然后, 以色胺酮6位酮羰基分别与水合肼、盐酸羟胺反应生成C环席夫碱结构. 最后, 以哌嗪结构取代B环嘧啶酮合成茚(1,2-b)喹喔啉-11-酮. 共设计合成20个化合物, 其中新化合物13个. 对所合成化合物的结构经红外光谱、核磁氢谱、元素分析确证. 测定所合成化合物对肿瘤细胞A549的体外抑制活性. 结果表明化合物1b, 1c, 1i, 1j, 1p1q表现出较强的肿瘤细胞抑制活性, IC50值分别为3.58, 0.99, 1.03, 2.10, 0.51和0.43 μmol·L-1. 构效关系研究表明: D环卤素取代提高抗肿瘤活性, 而取代基团在A环时则减弱抗肿瘤活性; B环(嘧啶环)被哌嗪环取代后抗肿瘤活性消失(IC50 >100 μmol·L-1); 而C环酮羰基生成席夫碱结构抗肿瘤活性与色胺酮相当.

关键词: 色胺酮, 吲哚醌, 邻氨基苯甲酸, 抗肿瘤活性

The isatin derivatives 4a4f were prepared and underwent oxidative hydrolysis to give the anthranilic acid 5a5d. A and/or D-ring substituted tryptanthrins were designed and synthesized from 4a4f to 5a5d. Then C-ring Schiff bases of tryptanthrin were synthesized by condensation of 6-carbonyl with hydrazine and hydroxylamine hydrochloride. Finally, the B-ring was replaced with piperazine to give 11H-indeno[1,2-b]quinoxalin-11-one. 20 compounds were synthesized and their structures were confirmed by 1H NMR, IR and elemental analysis. To best of our knowledge, 13 of them were unknown in the literature. The antitumor activities of synthesized compounds were evaluated against A549 cell line in vitro. The preliminary results indicated that 1b, 1c, 1i, 1j, 1p and 1q showed good antitumor activity with the IC50 of 3.58, 0.99, 1.03, 2.10, 0.51 and 0.43 μmol·L-1, respectively. Structure-activity relationship showed that halogen substitution located in the D-ring enhanced the anti-tumor activity, while the same substitution located in the A ring reduced the activity. The anti-tumor activity disappeared when B-ring was replaced by piperazine, while there was no significant difference for tryptanthrin and its C-ring Schiff base.

Key words: tryptanthrin, isatin, anthranilic acid, antitumor activity