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

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.