摘要/Abstract
为发现高效、低毒的抗肿瘤药物，以吡咯并[2，1-f][1，2，4]三嗪为母核，通过给母核的4，6-位引入不同的结构单元，设计、合成了11个新的吡咯并三嗪衍生物，并对其抑制肿瘤细胞增殖的活性进行了评价.目标化合物的合成先是以氰基乙酸甲酯为原料，经肟化、还原、酯的氨解三步反应制得2-氨基-2氰基乙酰胺（1）；同时通过乙酰乙酸乙酯和N，N-二甲基甲酰胺二甲缩醛之间的缩合反应制得2-乙酰基-3-（二甲基氨基）丙烯酸乙酯（2）；经化合物1与2之间的环化反应获得5-氰基-4-甲基吡咯-3-甲酸乙酯（4）.化合物4经氨化、脒的生成、Dimroth重排、水解和酰化反应分别获得目标化合物.利用噻唑蓝（MTT）比色法测试了目标化合物对肿瘤细胞的抗增殖活性，结果显示大部分合成化合物对高表达野生型表皮生长因子受体（EGFR）的人表皮鳞癌细胞A431具有一定的抗增殖作用.特别是4-（3-乙炔基苯氨基）-5-甲基吡咯并[2，1-f][1，2，4]三嗪-6-甲酸乙酯（7c）、4-（3-氯-4-（3-氟苄氧基）苯氨基）-5-甲基吡咯并[2，1-f][1，2，4]三嗪-6-甲酸（8a）和4-（3-乙炔基苯氨基）-5-甲基吡咯并[2，1-f][1，2，4]三嗪-6-（N-（2-（甲磺酰基）乙基））甲酰胺（9c）对A431肿瘤细胞的抗增殖活性较高，IC50值分别为20.05，21.98和23.87 μmol·L-1.初步的构效关系分析表明4-位芳氨基为3-氯-4-（3-氟苄氧基）苯氨基和3-乙炔基苯氨基时，能够增强4-芳氨基吡咯并三嗪-6-甲酸或其酯对A431肿瘤细胞增殖的抑制活性.
关键词: 吡咯并三嗪, 4-芳氨基吡咯并三嗪, Dimroth重排, 肿瘤, 抗增殖活性
In order to find novel antitumor agents with high efficiency and low toxicity, 11 novel pyrrolo[2,1-f] [1,2,4]triazine derivatives were designed and synthesized through the introduction of varied structural moieties to the 4,6-positions of pyrrolotriazine core. The antiproliferative activities of synthesized compounds were also evaluated against human tumor cells. Firstly, 2-amino-2-cyanoacetamide (1) was prepared from methyl cyanoacetate as a starting material through three step reactions of oximation, reduction and ammonolysis. Meanwhile, ethyl 2-acetyl-3-(dimethylamino)acrylate (2) was obtained from the reaction of ethyl acetoacetate with N,N-dimethylformamide dimethyl acetal. Then the cyclization reaction of 1 with 2 gave ethyl 5-cyano-4-methylpyrrole-3-carboxylate (4). Finally, pyrrolotriazine derivatives as target compounds were synthesized from 4 through the ammoniation, generating amidine, Dimroth rearrangement, and subsequent hydrolyzation and acylation. The antiproliferative activities of target compounds against human tumor cell lines were investigated by methyl thiazolyl tetrazolium (MTT) colorimetric assay. The results demonstrated that most synthesized compounds had obviously selective inhibitory effects against A431 cells with highly expressed wild type epidermal growth factor receptor (EGFR). Ethyl 4-(3-ethynylphenylamino)-5-methylpyrrolo[2,1-f] [1,2,4]triazine-6-carboxylate (7c), 4-(3-chloro-4-(3-fluorobenzyloxy)phenyl-amino)-5-methylpyrrolo[2,1-f] [1,2,4]triazine-6-carboxylic acid (8a) and 4-(3-ethynylphenylamino)-5-methylpyrrolo[2,1-f]-[1,2,4]triazine-6-(N-(2-(methylsulfonyl)ethyl))carboxamide (9c) were the most potent agents with IC50 values of 20.05, 21.98 and 23.87 μmol·L-1 in the synthesized compounds, respectively. Preliminary structure-activity relationship analysis indicated that the introduction of 3-chloro-4-(3-fluorobenzyloxy)phenylamino and 3-ethynylphenylamino to 4-position of pyrrolotriazine-6-carboxylic acids or its esters can lead to enhance antiproliferative activities against A431 tumour cells.
Key words: pyrrolotriazine, 4-arylaminopyrrolotriazine, Dimroth rearrangement, tumor, antiproliferative activity
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