凡德他尼衍生物的设计、合成与体外抗肿瘤活性  

Design, synthesis and in vitro antitumor activity of vandetanib derivatives

作　　者：张芮[1] 夏桂民[1] 吕凯[1] 柳珊[1] 张俊[1,2] 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)

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所有机化学室,北京100050 [2]浙江司太立制药股份有限公司,仙居317300

出　　处：《中国医药生物技术》2016年第5期432-436,共5页Chinese Medicinal Biotechnology

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.

关 键 词：化学技术 合成 抗代谢药 抗肿瘤 凡德他尼衍生物 

分 类 号：R91[医药卫生—药学] R914.5R96