摘要
目的设计合成凡德他尼衍生物,并评价其体外抗肿瘤活性。方法 4-(2-氟-4-溴)苯胺基喹唑啉母核化合物(由7-苄氧基-6-甲氧基喹唑啉-4-醇合成)与含有肟基的哌啶类化合物(由N-Boc-3/4-哌啶酮合成)通过缩合反应制备目标物,其结构经1H-NMR、13C-NMR、MS和HRMS确证。SRB法测定所有目标物(30μmol/L)对肺癌细胞A549的抑制率,进一步测定抑制率大于65%的目标物对4种肿瘤细胞A549、HT29、K562、KB的IC_(50)值。结果合成了20个全新结构的凡德他尼衍生物。7个目标物对A549的抑制率大于65%,其中化合物15b1和16b2对A549的IC_(50)分别为1.94和0.26μmol/L,化合物15b2对口腔表皮癌细胞KB的IC_(50)为4.83μmol/L,优于或相当于凡德他尼。结论丰富了凡德他尼7-位取代基的结构类型,目标物16b2对A549的活性是凡德他尼的6倍以上,值得进一步研究。
Objective To design and synthesize a series of novel vandetanib derivatives, and evaluate their in vitro antitumor activity. Methods Title compounds were synthesized through the condensation of 4-（（4-bromo-2-fluorophenyl）amino）-6-methoxyquinazolines, which were prepared from 7-（benzyloxy）-6-methoxyquinazolin-4-ol, and piperidines obtained from N-Boc-3/4-piperidones. Their structures were characterized by ^1H-NMR, ^13C-NMR, MS and HRMS. In vitro antitumor activity of the title compounds were evaluated by SRB assay. Results Twenty novel compounds were synthesized in this work. Among them, seven compounds（at 30 μmol/L） were found to have 65% inhibition against A549 cell line. Compounds 15b1（IC_（50）： 1.94 μmol/L） and 16b2（IC_（50）： 0.26 μmol/L） against A549 cells and compound 15b2（IC_（50）： 4.83 μmol/L） against KB cells were more active than or comparable to vandetanib. Conclusion The structure skeletons at C-7 position of vandetanib were enriched. Compound 16b2 with much higher activity than vandetanib against A549 cells is worthy of further research.
作者
张芮
夏桂民
吕凯
柳珊
张俊
刘明亮
ZHANG Rui XIA Gui-min LU Kai LIU Shan ZHANG Jun LIU Ming-liang(Department of Medicinal Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences ＆ Peking Union Medical College, Beijing 100050, China Zhejiang Starry Pharmaceutical Co. Ltd., Xianju 317300, China)
出处
《中国医药生物技术》
2016年第5期432-436,共5页
Chinese Medicinal Biotechnology
关键词
化学技术
合成
抗代谢药
抗肿瘤
凡德他尼衍生物
Chemistry techniques
synthetic
Antimetabolites
antineoplastic
Vandetanib derivatives
