以碘喹唑啉支架为基础合成了表皮生长因子受体(EGFR)T790M/血管内皮生长因子受体-2(VEGFR-2)的新型抑制剂,芳香,和/或脂族部分。在体外检查了新型衍生物对A549,HCT116,密歇根州癌症基金会-7(MCF-7)的抗癌活性,和HepG2细胞。应用分子建模来发现它们与VEGFR-2和EGFR活性位点两者的结合方向。化合物8d,8c,6d,和6c显示最高的细胞毒性,IC50=6.00、6.90、6.12和6.24µM,7.05、7.35、6.80和6.80µM,5.75、7.50、6.90和6.95µM,和6.55,7.88,7.44和7.10µM对A549,HepG2,HCT116和MCF-7细胞系,相应地。评价了极具活性的八种化合物6a-d和8a-d对正常VERO(正常非洲绿猴肾细胞)的细胞毒性。我们的化合物对正常VERO细胞表现出低毒性,IC50=45.66-51.83μM。此外,对所有化合物进行EGFRT790M和VEGFR-2酶的抑制试验.化合物6d对EGFRT790M活性有显著的抑制作用,8d,6c,和8c,IC50分别为0.35、0.42、0.48和0.50µM。此外,化合物8d对VEGFR-2活性有显著抑制作用,8c,6d,和6c,IC50分别为0.92、0.95、1.00和1.20µM。按计划,导数6d,8d,6c,和8c表现出对EGFRT790M/VEGFR-2两种活性的异常抑制。最后,在硅吸收中,分布,新陈代谢,对高活性的四种化合物6c进行了排泄和毒性(ADMET)研究,6d,8c,和8d比较,以厄洛替尼和索拉非尼为参考标准。
Novel inhibitors of epidermal growth factor receptor (EGFR)T790M/vascular endothelial growth factor receptor-2 (VEGFR-2) were synthesized based on the iodoquinazoline scaffold linked to different heteroaromatic, aromatic, and/or aliphatic moieties. The novel derivatives were in vitro examined for anticancer activities against A549, HCT116, michigan cancer foundation-7 (MCF-7), and HepG2 cells. Molecular modeling was applied to discover their orientation of binding with both VEGFR-2 and EGFR active sites. Compounds 8d, 8c, 6d, and 6c indicated the highest cytotoxicity with IC50 = 6.00, 6.90, 6.12 and 6.24 µM, 7.05, 7.35, 6.80, and 6.80 µM, 5.75, 7.50, 6.90, and 6.95 µM, and 6.55, 7.88, 7.44, and 7.10 µM against the A549, HepG2, HCT116, and MCF-7 cell lines, correspondingly. The cytotoxicity against normal VERO (normal african green monkey kidney cells) of the extremely active eight compounds 6a-d and 8a-d was evaluated. Our compounds exhibited low toxicity concerning normal VERO cells with IC50 = 45.66-51.83 μM. Furthermore, inhibition assays for both the EGFRT790M and VEGFR-2 enzymes were done for all compounds. Remarkable inhibition of EGFRT790M activity was achieved with compounds 6d, 8d, 6c, and 8c at IC50 = 0.35, 0.42, 0.48, and 0.50 µM correspondingly. Moreover, remarkable inhibition of VEGFR-2 activity was achieved with compounds 8d, 8c, 6d, and 6c at IC50 = 0.92, 0.95, 1.00, and 1.20 µM correspondingly. As planned, derivatives 6d, 8d, 6c, and 8c presented exceptional inhibition of both EGFRT790M/VEGFR-2 activities. Finally, in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were made for the highly active four compounds 6c, 6d, 8c, and 8d in comparison with erlotinib and sorafenib as reference standards.