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有机化学
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有机化学 ›› 2018, Vol. 38 ›› Issue (5): 1233-1241.DOI: 10.6023/cjoc201708027 上一篇    下一篇

研究论文

基于烯胺腈结构的吡喃香豆素并嘧啶类化合物的合成及抗肿瘤活性研究

黄新炜a, 刘建利b   

  1. a 西安文理学院化学工程学院 西安 710065;
    b 西北大学生命科学学院 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 西安 710069
  • 收稿日期:2017-08-14 修回日期:2017-10-31 发布日期:2018-01-03
  • 通讯作者: 黄新炜,E-mail:huangxinw@sina.com E-mail:huangxinw@sina.com
  • 基金资助:

    西安市科技计划（No.CXY1443WL13）及陕西省教育厅基金（No.15JK2145）资助项目.

Synthesis and Anticancer Activities of Novel Pyranocoumarin Fused Pyrimidine Based on Cyanoenamine

Huang Xinweia, Liu Jianlib   

  1. a School of Chemical Engineering, Xi'an University, Xi'an 710065;
    a Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Science, Northwest University, Xi'an 710069
  • Received:2017-08-14 Revised:2017-10-31 Published:2018-01-03
  • Contact: 10.6023/cjoc201708027 E-mail:huangxinw@sina.com
  • Supported by:

    Project supported by the Science and Technology Program of Xi'an City (No. CXY1443WL13) and the Foundation of the Education Department of Shaanxi Province (No. 15JK2145).

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吡喃香豆素是一类重要的天然产物，具有广泛的生物活性和药理作用，如抗肿瘤、抗菌、抗人类免疫缺陷病毒（HIV）、抗炎、抗氧化等.嘧啶是另一类重要的含氮杂环化合物，利用药物设计中的药效团拼合原则，如将吡喃香豆素和嘧啶结构进行拼合，有可能获得抗肿瘤活性更好的先导化合物.因此，首先以4-羟基香豆素、芳香醛、丙二腈为原料，4-二甲氨基吡啶（DMAP）为催化剂，通过多组分反应合成具有烯胺腈结构的吡喃香豆素，再与N，N-二甲基甲酰胺二甲缩醛（DMF-DMA）反应制备N，N-二甲基甲脒，最后与芳香胺通过Dimroth重排制备新型4-苯胺基取代吡喃香豆素并嘧啶类化合物，并通过熔点，IR，1H NMR，13C NMR，元素分析对目标产物的结构进行了表征，所得目标产物均未见文献报道.该方法具有反应时间短、反应条件温和、操作简单、产率高、无需柱色谱分离等优点.通过四甲基偶氮唑盐微量酶反应比色法（MTT）对目标产物抑制人宫颈癌细胞Hela和人急性早幼粒白血病细胞HL-60的活性进行了体外评价，结果表明：化合物4-（4'-溴苯胺基）-5-（2'，3'-二氯苯基）-色烯[3'，4'：5，6]吡喃[2，3-d]嘧啶-6-酮（4k）和4-（4'-溴苯胺基）-5-（4'-硝基苯基）-色烯[3'，4'：5，6]吡喃[2，3-d]嘧啶-6-酮（4l）对HL-60具有较高活性，其IC50分别为（11.3±0.3）和（10.8±0.2）μmol/L；化合物4-（4'-氯苯胺基）-5-（3'，4'，5'-三甲氧苯基）-色烯[3'，4'：5，6]吡喃[2，3-d]嘧啶-6-酮（4g）和4-（3'-氯-4'-氟苯胺基）-5-（3'，4'，5'-三甲氧苯基）-色烯[3'，4'：5，6]吡喃[2，3-d]嘧啶-6-酮（4h）对Hela具有较高活性，其IC50分别为（9.2±0.6）和（8.5±0.2）μmol/L.

关键词: 吡喃香豆素并嘧啶, 烯胺腈, 合成, 抗肿瘤活性

Pyranocoumarin is an important kind of natural products, which has many biological activities and pharmacological effects, such as antitumor, anti-bacterial, anti-human immunodeficiency virus (HIV), anti-inflammatory, antioxidation, etc. Pyrimidine is another important nitrogen-containing heterocycles. Using the pharmacophore combination principle of drug design, it is possible to obtain lead compounds with better anticancer activities by puting pyranocoumarin and pyrimidine structures together. Therefore, pyranocoumarin which has cyanoenamine structure was synthesized by multicomponent reaction, taking 4-hydroxycoumarin, aromatic aldehyde, malononitrile as raw materials and 4-dimethylaminopyridine (DMAP) as catalyst. Then N, N-dimethyl formamidine derivatives were synthesized by treatment with dimethylformamide-dimethyl acetal. Finally 4-anilino substituted pyranocoumarin fused pyrimidines were synthesized by treatment with substituted anilines involving Dimroth rearrangement. The structures of target compounds were characterized by melting point, IR, 1H NMR, 13C NMR and elemental analysis. This method has some advantages with short reaction time, mild reaction condition, simple operation, high yields and with no chromatographic separation procedure. All the title compounds were evaluated for anticancer activities in vitro against HL-60 cell lines and Hela human cervical cartcinoma cell lines. The results showed that 4-(4'-bromophenylamino)-5-(2', 3'-dichlorophenyl)-chromene [3', 4':5, 6]pyrano [2, 3-d]pyrimidin-6-one (4k) and 4-(4'-bromo- phenylamino)-5-(4'-nitrophenyl)-chromene [3', 4':5, 6]pyrano [2, 3-d]pyrimidin-6-one (4l) exhibited high activity against HL-60 with IC50 values of (11.3±0.3) and (10.8±0.2) μmol/L, and 4-(4'-chlorophenylamino)-5-(3', 4', 5'-trimethoxyphenyl)- chromene [3', 4':5, 6]pyrano [2, 3-d]pyrimidin-6-one (4g) and 4-(3'-chloro-4'-fluorophenylamino)-5-(3', 4', 5'-trimethoxy- phenyl)-chromene [3', 4':5, 6]pyrano [2, 3-d]pyrimidin-6-one (4h) exhibited high activity against Hela with IC50 value of (9.2±0.6) and (8.5±0.2) μmol/L.

Key words: pyranocoumarin fused primidine, cyanoenamine, synthesis, anticancer activity