摘要/Abstract

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


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