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  

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

作　　者：苑睿[1] 崔浩 陈雯 任璇璇 周杭 徐慧 孙雅文 梁燕妮 宛瑜[1] 刘金娟[1] 吴翚[1,2] Yuan Rui;Cui Hao;Chen Wen;Ren Xuanxuan;Zhou Hang;Xu Hui;Sun Yawen;Liang Yanni;Wan Yu;Liu Jinjuan;Wu Hui(Key Laboratory of Biotechnology for Medicinal Plant of Jiangsu Province,Jiangsu Normal University,Xuzhou,Jiangsu 221116;School of Chemistry and Chemical Engineering,Jiangsu Normal University,Xuzhou,Jiangsu 221116)

机构地区：[1]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 [2]江苏师范大学化学与材料科学学院,江苏徐州221116

出　　处：《有机化学》2020年第4期1017-1027,共11页Chinese Journal of Organic Chemistry

基　　金：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);江苏省研究生科研创新计划(Nos.KYCX18_2111,KYCX18_2116)资助项目.

摘　　要：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.1,7-Bis(N-substituted-aminomethyl)-2,8-dihydroxy-Tr?ger’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).Subsequently,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(inhibition rate>30%)on MCF-7 cells while 1,7-bis(((1-phenylethyl)amino)methyl)-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-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]chromene-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.

关 键 词：Tröger碱 Aldol-Ullmann反应 抗肿瘤活性 

分 类 号：TQ463[化学工程—制药化工]