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2020 , Vol. 40 >Issue 2: 391 - 397

DOI: https://doi.org/10.6023/cjoc201907006

研究论文

含吲哚的吡唑并[3,4-d]嘧啶衍生物的设计合成及其生物活性研究

  • 孙晓阳 ,
  • 冯思冉 ,
  • 董金娇 ,
  • 冯佳佳 ,
  • 刘振明 ,
  • 宋亚丽 ,
  • 乔晓强
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  • a 河北大学药学院 河北省药物质量分析控制重点实验室 河北保定 071000;
    b 沧州市中心医院 国家药物临床试验机构 河北沧州 061000;
    c 北京大学药学院 天然药物及仿生药物国家重点实验室药物设计中心 北京 100191;
    d 河北大学 药物化学与分子诊断教育部重点实验室 河北保定 071000

收稿日期: 2019-07-03

  修回日期: 2019-09-11

  网络出版日期: 2019-11-01

基金资助

河北省自然科学基金（No.B2018201269、河北省高等学校科学技术研究项目（No.ZD2019060）、国家自然科学基金（No.21675039）、河北省青年拔尖人才资助项目.

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Design, Synthesis and Biological Activity of Pyrazolo[3,4-d]pyrimidine Derivatives Containing Indole Moiety

  • Sun Xiaoyang ,
  • Feng Siran ,
  • Dong Jinjiao ,
  • Feng Jiajia ,
  • Liu Zhenming ,
  • Song Yali ,
  • Qiao Xiaoqiang
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  • a Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacetical Sciences, Hebei University, Baoding, Hebei 071000;
    b National Drug Clinical Trial Institution, Cangzhou Central Hospital, Cangzhou, Hebei 061000;
    c Drug Design Center, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191;
    d Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding, Hebei 071000

Received date: 2019-07-03

  Revised date: 2019-09-11

  Online published: 2019-11-01

Supported by

Project supported by the Natural Science Foundation of Hebei Province (No. B2018201269), the Research Award Fund Scientific and Technological in Higher Education Institutions of Hebei Province (No. ZD2019060), the National Natural Science Foundation of China (No. 21675039), and the Young Talent of Hebei Province.

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摘要

利用药物设计中的生物活性基团拼接原理，设计合成了13个含吲哚的吡唑并[3，4-d]嘧啶衍生物.目标化合物均经核磁共振氢谱（1H NMR）、核磁共振碳谱（13C NMR）和高分辨质谱仪（HRMS）进行了结构确证.对4株肿瘤细胞（HeLa、MGC-803、MCF-7、BEL-7404）的体外抗增殖活性实验结果表明，目标化合物均表现出一定的抗肿瘤活性，MCF-7、MGC-803肿瘤细胞株敏感度高于HeLa和BEL-7404.其中，6-[（6-甲氧羰基吲哚-3-基）硫基]-1-苯基-吡唑并[3，4-d]嘧啶-4-酮（5m）表现出较好的体外肿瘤抑制活性，对MCF-7、MGC-80和HeLa细胞的IC50均小于30 μmol·L-1，对MCF-7的IC50值为（4.02±0.92）μmol·L-1，优于对照药物依托泊苷（10.1±0.62 μmol·L-1）和羟喜树碱（5.93±0.56 μmol·L-1）.拓扑异构酶抑制实验结果表明，此类化合物对TopoII有选择性抑制活性，所有化合物对Topo II表现出不同程度抑制活性，对Topo I未表现出抑制活性.

关键词： 吲哚; 吡唑并[3,4-d]嘧啶; 抗肿瘤; 拓扑异构酶; 分子对接

本文引用格式

孙晓阳 , 冯思冉 , 董金娇 , 冯佳佳 , 刘振明 , 宋亚丽 , 乔晓强 . 含吲哚的吡唑并[3,4-d]嘧啶衍生物的设计合成及其生物活性研究[J]. 有机化学, 2020 , 40(2) : 391 -397 . DOI: 10.6023/cjoc201907006

Abstract

Based on the combination principle in drug design, thirteen pyrazolo[3,4-d]pyrimidine derivatives containing indole moiety were designed and synthesized. The target compounds were confirmed by 1H NMR, 13C NMR and HRMS. Their in vitro cytotoxicity against four human cancer cell lines (HeLa、MGC-803、MCF-7、BEL-7404) has been investigated and most of the tested compounds displayed moderate antiproliferative activity. Especially, compound 5m exhibited the highest level of antiproliferative activity with an IC50 value <30 μmol·L-1 for HeLa, MGC-803 and MCF-7. IC50 value of methyl 3-((4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)thio)-1H-indole-6-carboxylate (5m) to MCF-7 was (4.02±0.92) μmol·L-1, which was better than etoposide (10.1±0.62 μmol·L-1) and camptothecin (5.93±0.56 μmol·L-1). Further biological evaluation of these compounds suggested that these compounds showed selective inhibitory activity against Topo II as a possible intracellular target, and all compounds didn't show inhibitory activity against Topo I.

Key words： indole; pyrazolo[3,4-d]pyrimidine; anticancer; topoisomerase; molecular docking

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