吲哚脲类化合物的设计合成及其体外抗肿瘤活性研究  

Design,synthesis and in vitro antitumor activity of indole urea derivatives

作　　者：邵现奇 唐克[1] 李鹏[1] 李燕[1] 林紫云[1] 尹大力[1] 陈晓光[1] 黄海洪[1] 

机构地区：[1]中国医学科学院北京协和医学院药物研究所活性物质发现与适药化北京市重点实验室,北京100050

出　　处：《中国药物化学杂志》2013年第4期253-261,共9页Chinese Journal of Medicinal Chemistry

摘　　要：目的以索拉非尼为先导物,设计并合成一系列吲哚脲类化合物,并对其体外抗肿瘤活性进行初步评价。方法以5-硝基吲哚-2-甲酸为起始原料,采用BOP法合成酰胺,再将硝基还原成胺基,最后与异氰酸酯缩合,共3步反应制备目标化合物;采用MTT法评价目标化合物对4种肿瘤细胞株(MX-1、A375、HepG2、Ketr3)的生长抑制作用。结果与结论合成了28个吲哚脲类新化合物,其结构经1H-NMR和HR-MS确证。体外活性结果表明,与索拉非尼相比多数化合物选择性地作用于MX-1细胞株,显示出较强的抑制肿瘤细胞增殖的活性。其中含甲基哌啶的化合物26、30和31抑制MX-1和A375细胞生长的作用显著强于索拉非尼。尤其是化合物31抑制A375细胞增殖的作用是索拉非尼的10倍,对HepG2的抑制活性与索拉非尼相当,IC50值均达到微摩尔级水平,值得进一步研究。Twenty-eight indole uera derivatives were designed and synthesized based on the structural modification of sorafenib. The target compounds were prepared via three steps including amidation, reduction and condensation with 5-nitroindole-2-carboxylic acid as the starting material, and their chemical structures were confirmed by 1H-NMR and HR-MS. The in vitro antitumor activity of these target compounds was evaluated by the MTT assay against MX-1 ,A375, HepG2 and Ketr3 human tumor cell lines. Most of the synthesized compounds displayed selective antiproliferative activity against MX-1 cells compared to the positive control sorafenib. It was worth noting that compounds 26,30 and 31 bearing methylpiperidyl moiety showed more potent inhibitory activity than that of sorafenib on MX-1 and A375 cell lines. Particularly, compound 31 possessed comparable activity to sorafenib on HepG2 ,but 10-fold higher than sorafenib on A375 cells with IC50 values at micromolar level. Compound 31 could serve as a new lead for further investigation.

关 键 词：索拉非尼 吲哚脲类化合物 合成 抗肿瘤活性 

分 类 号：R914[医药卫生—药物化学]