凡德他尼衍生物的抗肿瘤活性筛选研究

目的对合成的一系列凡德他尼衍生物进行体内外抗肿瘤活性的筛选,为寻找低毒高效的新型酪氨酸激酶抑制剂研究提供依据。方法体外筛选采用均相时间分辨荧光(HTRF)法和磺酰罗丹明B(SRB)法分别进行激酶和细胞的筛选;采用经典的急性毒性实验方法,并建立移植人非小细胞肺癌H1975裸鼠模型评价其抗肿瘤活性。结果 HTRF结果显示有6个活性较好的化合物(TY8115、TY8119、TY8122、TY8128、TY8129、TY8131),其中TY8115对VEGFR-2和EGFR抑制作用均好于凡德他尼;SRB结果显示这些活性化合物对选用的3种靶细胞(A431、H1975、A549)均有不同程度的抑制作用,其中TY8115的肿瘤细胞增殖抑制作用最明显,且对非靶细胞(MDA-MB-231)生长影响很小;急性毒性实验结果显示TY8115没有表现出毒性反应;体内抗肿瘤活性研究结果显示TY8115对肺癌H1975具有疗效,75、150 mg/kg TY8115对H1975的相对肿瘤增殖率分别为54.44%、39.54%。结论化合物TY8115具有良好的抗肿瘤活性,并且毒副作用小,具有发展成为一种新型酪氨酸激酶抑制剂的潜力。

Screening of anti-tumor activity of vandetanib derivatives

Objective To screen the antitumor activity in vivo and in vitro of the series of vandetanib derivatives, and to provide the basis for seeking new tyrosine kinase inhibitors with high efficiency and low toxicity. Methods Homogeneous time-resolved fluorescence (HTRF) and SRB method were used to screen kinases and cells in vitro; The acute toxicity experiment of classical methods was used, and nude mice model transplanted by non-small cell lung cancer H1975 cells was established to evaluate the antitumor activity. Results Six compounds (TY8115, TY8119, TY8122, TY8128, TY8129, and TY8131) with better activities were selected by HTRF method, where TY8115 had better inhibitory effect onVEGFR-2 and EGFR than vandetanib. The above active compounds showed different degrees of inhibition on three kinds of target cells (A431, H1975, and A549) by SRB method, and the inhibition of TY8115 was the most obvious. TY8115 had little impact on the non target cell (MDA-MB-231) growth. Results of acute toxicity test showed that TY8115 exhibited no toxicity. Antitumor activity in vivo showed that TY8115 with doses of 75 and 150 mg/kg had curative effect on lung cancer H1975 cells with relative tumor growth rates of 54.44% and 39.54%, respectively. Conclusion The compound TY8115 has good antitumor activity in vitro and in vivo, and has no previous toxicity, which will be an new tyrosine kinase inhibitor.