4-苯氨基喹啉化合物的合成及其与EGFR~(T790M)分子对接研究
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摘要
以6-氟(或7-氟)-4-氯-喹啉为原料与对二苯胺经亲核取代反应,得到4-(4'-氨基苯氨基)喹啉化合物,再与不同的酰化试剂发生酰化反应,得到12个未见文献报道的化合物,结构经过ESI-MS确认。用Molegro Virtual Docker软件完成与EGFR~(T790M)的分子对接,并用Discovery Studio 2016 Client软件分析化合物与EGFR~(T790M)的作用模式。分子对接研究表明6-氟-4-{4'-[(4″-甲氧基)-苯酰氨基]-苯氨基}-喹啉1位的氮和4″位甲氧基上的氧分别与ARG A:776和HIS A:850残基形成两个氢键。为开发EGFR~(T790M)抑制剂提供基础。
6-Fluoro( or 7-fluoro)-4-chloro-quinoline reacted with para diphenylamine to give 4-(4'-aminophenylamino) quinoline compounds by nucleophilic substitution reaction.Acylation of 4-(4'-aminophenyl amino) quinoline compounds with different acylation reagents yields twelve novel compounds.The structure of the target compunds was confirmed by ESI-MS.Molecular docking was performed with Molegro Virtual Docker software,The interaction between compounds and EGFR~(T790M) Mwas analyzed by Discovery Studio 2016 Client software.The Molecular docking showed that N of 1 position and O of 4″ position of 6-fluoro-4-{ 4'-[( 4″-methoxy)-benzoylamino]-phenylamino}-quinoline give a hydrogen bond with ARG A: 776 and HIS A: 850,respectively,which provides basis for developing EGFR~(T790M) Minhibitors.
6-Fluoro( or 7-fluoro)-4-chloro-quinoline reacted with para diphenylamine to give 4-(4'-aminophenylamino) quinoline compounds by nucleophilic substitution reaction.Acylation of 4-(4'-aminophenyl amino) quinoline compounds with different acylation reagents yields twelve novel compounds.The structure of the target compunds was confirmed by ESI-MS.Molecular docking was performed with Molegro Virtual Docker software,The interaction between compounds and EGFR~(T790M) Mwas analyzed by Discovery Studio 2016 Client software.The Molecular docking showed that N of 1 position and O of 4″ position of 6-fluoro-4-{ 4'-[( 4″-methoxy)-benzoylamino]-phenylamino}-quinoline give a hydrogen bond with ARG A: 776 and HIS A: 850,respectively,which provides basis for developing EGFR~(T790M) Minhibitors.
引文
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[3]齐敬敬,孙春艳,褚岩凤,等.HPLC法测定吉非替尼原料药有关物质[J].药物分析杂志,2016,36(4):704-710.
[4]刘宇,夏超,刘媛.抗癌药凡德他尼的合成[J].中国抗生素杂志,2011,36(12):917-920.
[5]涂远彪,王敏,朱五福.阿法替尼的合成路线图解[J].华西药学杂志,2016,31(3):317-320.
[6]张庆文,周后元,尤启冬.拉帕替尼合成工艺研究[J].中国药科大学学报,2010,41(4):317-320.
[7]REWCASTLE G W,DENNY W A,BRIDGE A J,et al.Tyrosine kinase inhibitors.5.Synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]-and 4-(phenylamino)quinazolines as potent adenosine 5'-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor[J].J.Med.Chem.,1995,38(18):3 482-3 487.
[8]WISSNER A,FLOY B,RABINDRAN S K,et al.Syntheses and EGFR and HER-2 kinase inhibitory activities of4-anilinoquinoline-3-carbonitriles:analogues of three important 4-anilinoquinazolines currently undergoing clinical evaluation as therapeutic antitumor agents[J]. Bioorg.Med.Chem.Lett.,2002,12(20):2 893-2 897.
[9]LI R D,ZHAI X,ZHAO Y F,et al. Synthesis and antitumor activities of a novel series of tricyclic1-anilino-5Hpyridazino[4,5-b]indole[J]. Arch. Pharm. Chem. Life Sci.,2007,340(8):424-428.
[10]YANG S H,KHADKA D B,CHO S H,et al. Virtual screening and synthesis of quinazolines as novel JAK2inhibitors[J]. Bioorgan. Med. Chem.,2011,19(2):968-977.