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有机化学
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有机化学 ›› 2020, Vol. 40 ›› Issue (4): 1017-1027.DOI: 10.6023/cjoc201909026 上一篇    下一篇

研究论文

1,7-双(N-取代氨基甲基)-2,8-二羟基-朝格尔碱的合成及其催化的Aldol-Ullmann反应

苑睿a, 崔浩b, 陈雯b, 任璇璇b, 周杭b, 徐慧b, 孙雅文b, 梁燕妮b, 宛瑜a, 刘金娟a, 吴翚a,b   

  1. a 江苏师范大学省药用植物生物技术重点实验室 江苏徐州 221116;
    b 江苏师范大学化学与材料科学学院 江苏徐州 221116
  • 收稿日期:2019-09-17 修回日期:2019-11-06 发布日期:2020-05-06
  • 通讯作者: 吴翚, 宛瑜, 刘金娟 E-mail:wuhui72@jsnu.edu.cn;853270845@qq.com;jjlbest@jsnu.edu.cn
  • 基金资助:
    江苏省高校优势学科建设工程、江苏省高等学校自然科学研究（No.19KJB430019）、徐州市科技计划项目（No.KC19242）、江苏师范大学博士学位教师科研支持（No.17XLR023）和江苏省研究生科研创新计划（Nos.KYCX18_2111，KYCX18_2116）资助项目.

Synthesis of 1,7-Bis(N-substituted-aminomethyl)-2,8-dihydroxy-Tröger's Bases and Their Application in Aldol-Ullmann Reaction

Yuan Ruia, Cui Haob, Chen Wenb, Ren Xuanxuanb, Zhou Hangb, Xu Huib, Sun Yawenb, Liang Yannib, Wan Yua, Liu Jinjuana, Wu Huia,b   

  1. a Key Laboratory of Biotechnology for Medicinal Plant of Jiangsu Province, Jiangsu Normal University, Xuzhou, Jiangsu 221116;
    b School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou, Jiangsu 221116
  • Received:2019-09-17 Revised:2019-11-06 Published:2020-05-06
  • Supported by:
    Project supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions, the Natural Science Research Projects in Universities of Jiangsu Province (No. 19KJB430019), the Science and Technology Foundation of Xuzhou City (No. KC19242), the Aid Project for PhD Faculties in Jiangsu Normal University (No. 17XLR023) and the Graduate Student Scientific Research Innovation Projects in Jiangsu Province (Nos. KYCX18_2111, KYCX18_2116).

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合成了新型1，7-双（N-取代氨基甲基）-2，8-二羟基-朝格尔碱（4），以4为催化剂催化了4-羟基香豆素和2-亚苄基丙二腈[或甲基（乙基）-2-氰基-3-苯基丙烯酸]的Aldol反应，获得了一系列化合物8；以4为配体与钯联合催化了串联Aldol-Ullmann反应，得到了化合物10和12.测试了所有化合物对人三阳性乳腺癌细胞（MCF-7）、人三阴性乳腺癌细胞（MDA-MB-231）、人肝癌细胞（HepG2）和人肝癌细胞（MHCC-97H）的抗癌活性以及对人肝细胞（LO2）的细胞毒性.其中，1，7-双（（甲基氨基）甲基）-6H，12H-5，11-甲二苯并[b，f][1，5]二氮芳辛-2，8-二醇（4b）对MCF-7（抑制率>30%）、1，7-双（（（（1-苯乙基）氨基）甲基）-6H，12H-5，11-甲二苯并[b，f][1，5]二氮芳辛-2，8-二醇（4d）和1，7-双（（（吡啶-2-基甲基）氨基）甲基）-6H，12H-5，11-甲基二苯并[b，f][1，5]重氮-2，8-二醇（4e）对MDA-MB-231具有较高的选择性和抑制活性，2-氨基-5-氧代-4-（3，4，5-三甲氧基苯基）-4H，5H-二氢吡喃并[3，2-c]亚甲基-3-腈（8q）对除MDA-MB-231外其他癌细胞均具有很强的抑制活性，而2-氨基-4-（4-溴苯基）-5-氧代-4H，5H-吡喃并[3，2-c]亚甲基-3-腈（8a），2-氨基-4-（2，4-二氯苯基）-5-氧代-4H，5H-二氢吡喃[3，2-c]亚甲基-3-腈（8e），2-氨基-4-（3-氟苯基）-5-氧代-4H，5H-吡喃[3，2-c]亚甲基-3-腈（8m）和2-氨基-4-（3-溴苯基）-5-氧代-4H，5H-二氢吡喃[3，2-c]亚甲基-3-腈（8n）对四种癌细胞均具有较高的抑制率，但所有的化合物对正常人细胞都具有细胞毒性，需要对其结构进行修饰.

关键词: Tröger碱, Aldol-Ullmann反应, 抗肿瘤活性

1,7-Bis(N-substituted-aminomethyl)-2,8-dihydroxy-Tröger's bases (4) were synthesized and used as efficient organocatalyst for the Aldol reaction of 4-hydroxylcoumarin and 2-benzylidenemalononitrile (or methyl(ethyl)-2-cyano-3-phenylacrylate) to afford 2-amino-4-aryl-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitriles (carboxylates) (8). Subse-quently, they were used as the efficient ligand to promote the Pd-catalyzed Aldol-Ullmann reaction to give 7-aryl-7,12-dihydro-6H-chromeno[3',4':5,6]pyrano[2,3-b]indol-6-one (10) and 5'(or 5',7')-substituted-6H,12H-spiro[chromeno[3',4':5,6]-pyrano[2,3-b]indole-7,3'-indoline]-2',6-dione (12), respectively. The anti-cancer activity on human three positive breast cancer cells (MCF-7), human three negative breast cancer cells (MDA-MB-231), human hepatoma cells (HepG2), human hepatoma cells (MHCC-97H) and cytotoxicity on human hepatocyte cells (LO2) of catalyst 4 and all products in vitro were evaluated. 1,7-Bis((methylamino)methyl)-6H,12H-5,11-methanodibenzo[b,f] [1,5]diazocine-2,8-diol (4b) had selective inhibition (inhi-bition rate>30%) on MCF-7 cells while 1,7-bis(((1-phenylethyl)amino)methyl)-6H,12H-5,11-methanodibenzo[b,f] [1,5]diazo-cine-2,8-diol (4d) and 1,7-bis(((pyridin-2-ylmethyl)amino)methyl)-6H,12H-5,11-methanodibenzo[b,f] [1,5]diazocine-2,8-diol (4e) had selective inhibition on MDA-MB-231 cells. 2-Amino-5-oxo-4-(3,4,5-trimethoxyphenyl)-4H,5H-dihydropyrano[3,2-c]chromene-3-carbonitrile (8q) had strong inhibitory effects on three kinds of cancer cells except MDA-MB-231 while 2-amino-4-(4-bromophenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (8a), 2-amino-4-(2,4-dichlorophenyl)-5-oxo-4H,5H-dihydropyrano[3,2-c]chromene-3-carbonitrile (8e), 2-amino-4-(3-fluorophenyl)-5-oxo-4H,5H-pyrano[3,2-c]chrome-ne-3-carbonitrile (8m) and 2-amino-4-(3-bromophenyl)-5-oxo-4H,5H-dihydropyrano[3,2-c]chromene-3-carbonitrile (8n) had strong inhibitory effects on four kinds of cancer cells. However, all the compounds showed cytotoxicity to normal LO2 cells which prompts the necessary of structure modification to reduce the toxicity.

Key words: Tröger's base, Aldol-Ullmann reaction, anti-tumor activity