ZD6474衍生物筛选和抗肿瘤活性研究

目的 对自主研发的ZD6474衍生物进行抗肿瘤活性研究,从而为进一步的结构修饰、改造与药理学研究奠定良好的基础.方法 采用均相时间分辨荧光法以VEGFR-2、EGFR为检测靶点评价化合物的抑制活性；采用SRB法检测化合物对细胞的增殖抑制活性；移植人非小细胞肺癌H1299裸鼠模型作为体内抗肿瘤活性评价.结果 从大量化合物中筛选出4个有较好酪氨酸激酶抑制活性的化合物,分别编号为106、113、115、116.体外细胞实验结果显示化合物对肿瘤细胞生长增殖均有抑制作用,其中106对A431、H1975和A549细胞系均表现出良好的抑制活性.体内试验结果表明,106能够剂量依赖性抑制裸鼠肿瘤生长,且作用与ZD6474相当,25、75 mg/kg的106和ZD6474对H1299的相对肿瘤增殖率为57.3％、38.8％和52.5％、29.6％.结论 化合物106具有良好的体内外抗肿瘤作用,有进一步的研究价值.

Screening and anti-tumor activity study of ZD6474 derivatives

Objective To study the anti-tumor activity of new ZD6474 derivatives for further structural modification, renovation and pharmacological studies. Methods Homogeneous time-resolved fluorescence method （HTRF） was used to evaluate the compounds＇ inhibitory activity against VEGFR-2 and EGFR. Cell proliferation inhibition activity of the compounds was tested by SRB assay. Nude mice xenograft model of human NSCLC H1299 cells was used to test the compounds＇ anti-tumor activity in vivo. Results Four compounds, numbered as 106, 113, 115, 116, showed preferably tyrosine kinase inhibitory activity from the screening The compounds can inhibit tumor cell growth, among which No.106 compound showed most potent inhibitory activity in A431, H1975 and A549 cell lines. Moreover, No.106 compound dose-dependently inhibited tumor growth in vivo, showing comparable effects with that of ZD6474. When administered at dose of 25 and 75 mg/kg, the H1299 tumor inhibition rate was 57.3% and 38.8% for No. 106 compound, and was 52.5% and 29.6% for ZD6474, respectively. Conclusion The No. 106 compound has potent anti-tumor activity both in vitro and in vivo, and is worthy of further research.