目的 對合成的新型4-苯胺基喹唑啉類酪氨酸激酶抑制劑TYIG1～TYIG9進(jìn)行抗腫瘤活性研究，為尋找具有靶向抗腫瘤活性的候選化合物提供依據(jù)。方法 采用均相時間分辨熒光（HTRF）法對化合物進(jìn)行EGFR、VEGFR-2兩個靶點(diǎn)的體外活性篩選；采用MTS法對化合物進(jìn)行腫瘤細(xì)胞（A431、A549、H1975、MDA-MB-231）增殖抑制的體外活性評價；采用人肺癌H1975細(xì)胞的移植瘤裸鼠模型評價其在動物體內(nèi)抗腫瘤活性。結(jié)果 采用HTRF法從合成的一系列化合物中篩選出化合物TYIG4~TYIG9對EGFR、VEGFR-2激酶的活性較好。MTS法檢測得到這6個化合物對4種腫瘤細(xì)胞（A431、A549、H1975、MDA-MB-231）均有不同程度的抑制作用，其中TYIG6的增殖抑制作用的選擇性更為突出；體內(nèi)試驗(yàn)結(jié)果表明TYIG6能夠劑量相關(guān)性地抑制腫瘤生長，50、100 mg/kg TYIG6對H1975的相對腫瘤抑制率分別為42.59%、34.92%。結(jié)論 TYIG6具有良好的體內(nèi)外抗腫瘤活性，具有成為新型雙靶點(diǎn)酪氨酸激酶抑制劑的潛能，有進(jìn)一步的研究價值。

Objective To study the antitumor activity of synthesized 4-aminobenzene quinazoline tyrosine kinase inhibitors TYIG1 — TYIG9, 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.

天津市科技支撐計劃重點(diǎn)項(xiàng)目（13ZCZDSY00100）