N-(2-金刚烷-1H-吲哚-5-基)取代苯甲酰胺合成及生物活性研究
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摘要
以金刚烷甲酰氯为起始原料,亲核取代、环化、硝化和还原反应制得中间体2-金刚烷-5-氨基-1H-吲哚(5);再与取代酰氯反应,合成了5个N-(2-金刚烷-1H-吲哚-5-基)取代苯甲酰胺(6a—6e),其结构经1H NMR,13C NMR和HR-MS表征;采用四甲基偶氮唑盐(MTT)法研究了6a—6e对人肺癌细胞(A549)、人肝癌细胞(Hep G-2)和乳腺癌细胞(MCF-7)的体外抗肿瘤活性.结果显示:化合物6d体外抑制活性最优,其半数抑制浓度(IC50)分别为13. 45,11. 45,9. 56μmol/L.实验表明,化合物6d具有较好的抗肿瘤活性.
The intermediate 2-adamantane-5-amino-1 H-indole(5) was prepared from adamantine-substituted,cyclized,nitrated and reductive reactions using adamantyl chloride as starting material. Five N-(2-adamantane-1 H-indol-5-yl)-substituted benzamides(6 a—6 e) were synthesized by reaction with substituted acyl chlorides. Their structures were characterized by1 H NMR,13 C NMR and HR-MS. Tetramethyl azozolium salt(MTT)assay was used to study the in vitro antitumor activity of 6 a—6 e on human lung cancer cells(A549),human hepatoma cells( HepG-2) and breast cancer cells( MCF-7). The results showed that the optimal inhibitory activity in vitro reached at 6 d, with half inhibition concentration( IC50) of 13. 45,11. 45,9. 56 μmol/L respectively.
The intermediate 2-adamantane-5-amino-1 H-indole(5) was prepared from adamantine-substituted,cyclized,nitrated and reductive reactions using adamantyl chloride as starting material. Five N-(2-adamantane-1 H-indol-5-yl)-substituted benzamides(6 a—6 e) were synthesized by reaction with substituted acyl chlorides. Their structures were characterized by1 H NMR,13 C NMR and HR-MS. Tetramethyl azozolium salt(MTT)assay was used to study the in vitro antitumor activity of 6 a—6 e on human lung cancer cells(A549),human hepatoma cells( HepG-2) and breast cancer cells( MCF-7). The results showed that the optimal inhibitory activity in vitro reached at 6 d, with half inhibition concentration( IC50) of 13. 45,11. 45,9. 56 μmol/L respectively.
引文
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[5]Zhang M Z,Chen Q,Yang G F. A review on recent developments of indole-containing antiviral agents[J]. Eur J Med Chem,2015,89(6):421-441.
[6]Hu Hongyu,Wu Jun,Ao Mingtao,et al. Synthesis,structure-activity relationship studies and biological evaluation of novel 2,5-disubstituted indole derivatives as anticancer agents[J]. Chem Biol Drug Des,2016,88(5):766-778.
[7]Hu Hongyu,Yu Xudong,Wang Fei,et al. Novel N-substituted 2-(2-(adamantan-1-yl)-1H-Indol-3-yl)-2-oxoacetamide derivatives:Synthesis and biological evaluation[J]. Molecules,2016,21(5):1-15.
[8]Hu Hongyu,Lin Chunrong,Ao Mingtao,et al. Synthesis and biological evaluation of 1-(2-(adamantane-1-yl)-1H-indol-5-yl)-3-substituted urea/thiourea derivatives as anticancer agents[J]. Rsc Advances,2017,7(81):51640-51651.
[9]Houlihan W J,Parrino V A,Uike Y,et al. Lithiation of N-(2-alkylphenyl)alkanamides and related compounds. A modified Madelung indole synthesis[J]. J Org Chem,1981,46(22):4511-4515.
[10]Robinson M W,Overmeyer J H,Young A M,et al. S ynthesis and evaluation of indole-based chalcones as inducers of methuosis,a novel type of nonapoptotic cell death[J]. J Med Chem,2012,55(5):1940-1956.
[11]Barraza S J,Denmark S E. Unexpected rearrangement of 2-bromoaniline under biphasic alkylation conditions[J]. Synlett,2017,28(20):2891-2895.
[12]Ogiwara Y,Shimoda W,Ide K,et al. Carboxamides as N-alkylating reagents of secondary amines in indium-catalyzed reductive amination with a hydrosilane[J]. Eur J Med Chem,2017,2017(20):2866-2870.
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[14]陈仕杰,龚显峰,王雪微,等.伊马替尼衍生物的合成及细胞毒活性研究[J].化学通报,2015,35(7):621-626.
[15]高慧,郑喜,祁燕,等.新型白藜芦醇-查尔酮酰胺衍生物的合成及其细胞毒活性[J].有机化学,2018,38(3):648-655.