新型4-苯胺基喹唑啉类酪氨酸激酶抑制剂的抗肿瘤活性研究

目的对合成的新型4-苯胺基喹唑啉类酪氨酸激酶抑制剂TYIG1~TYIG9进行抗肿瘤活性研究,为寻找具有靶向抗肿瘤活性的候选化合物提供依据。方法采用均相时间分辨荧光（HTRF）法对化合物进行EGFR、VEGFR-2两个靶点的体外活性筛选;采用MTS法对化合物进行肿瘤细胞（A431、A549、H1975、MDA-MB-231）增殖抑制的体外活性评价;采用人肺癌H1975细胞的移植瘤裸鼠模型评价其在动物体内抗肿瘤活性。结果采用HTRF法从合成的一系列化合物中筛选出化合物TYIG4~TYIG9对EGFR、VEGFR-2激酶的活性较好。MTS法检测得到这6个化合物对4种肿瘤细胞（A431、A549、H1975、MDA-MB-231）均有不同程度的抑制作用,其中TYIG6的增殖抑制作用的选择性更为突出;体内试验结果表明TYIG6能够剂量相关性地抑制肿瘤生长,50、100 mg/kg TYIG6对H1975的相对肿瘤抑制率分别为42.59%、34.92%。结论 TYIG6具有良好的体内外抗肿瘤活性,具有成为新型双靶点酪氨酸激酶抑制剂的潜能,有进一步的研究价值。

Anti-tumor activity of novel 4-aminobenzene quinazoline tyrosine kinase inhibitors

Objective To study the antitumor activity of synthesized 4-aminobenzene quinazoline tyrosine kinase inhibitors TYIG 1 -- TYIGg, and provide the basis for seeking new targeting anti-tumor candidate compounds. Methods Homogeneous time-resolved fluorescence （HTRF） method was used to evaluate the inhibitory activity of the compounds against EGFR and VEGFR-2 in vitro. The activity study of cells （A431, A549, H1975, and MDA-MB-231） proliferation of the compounds was carried out by MTS method. Nude mice xenograft model of human NSCLC H1975 cells was used to evaluate the antitumor activity in vivo. Results In HTRF method, TYIG4 -- TYIG9 showed better activity from screening, which also had varying degrees of inhibition on cells （A431, A549, H1975, and MDA-MB-231） in MTS method. Among these six compounds, TYIG6 showed more obvious selectivity of inhibitory effects of cell proliferation, which could well restrain the tumor growth with dose-dependent tumor growth rates of 42.59% and 34.92% on doses of 50 and 100 mg/kg in vivo. Conclusion TYIG6 has good antitumor activity in vitro and in vivo, and needs more tests to further verify whether it can become a novel targeting tyrosine kinase inhibitor.