Design, synthesis and biological evaluation of novel 4-anilinoquinazolines with C-6 urea-linked side chains as inhibitors of the epidermal growth factor receptor.
Design, synthesis and biological evaluation of novel 4-anilinoquinazolines with C-6 urea-linked side chains as inhibitors of the epidermal growth factor receptor.
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DOI：
10.1016/j.bmc.2013.09.049
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发表时间：
2013-12
影响因子：
3.5
通讯作者：
Xu Zhang;Ting Peng;Xun Ji;Jian Li;Lin-jiang Tong;Zeng Li;Wei Yang;Yungen Xu;Meng-yuan Li;Jian Ding;Hualiang Jiang;Hua Xie;Hong Liu
中科院分区：
文献类型：
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作者：
Xu Zhang;Ting Peng;Xun Ji;Jian Li;Lin-jiang Tong;Zeng Li;Wei Yang;Yungen Xu;Meng-yuan Li;Jian Ding;Hualiang Jiang;Hua Xie;Hong Liu
基于苯胺基喹唑啉抑制剂的构效关系（SAR），设计并合成了一系列具有 C-6 脲连接侧链的新型苯胺基喹唑啉化合物，作为表皮生长因子受体（EGFR）的可逆抑制剂。所有化合物均表现出对 EGFR 野生型 (EGFR wt) 的良好抑制作用 (IC50= 0.024–1.715 μM) 并抑制 A431 细胞系的增殖 (IC50= 0.116–22.008 μM)。化合物8a、8d、8k和8ow的结合模式与生物学结果一致。此外，0.01 μM 的化合物 8k 和 8l 几乎完全阻断 A431 细胞系中 EGFR 的磷酸化。有趣的是，所有化合物还表现出对 EGFR/T790M/L858R 的中度抑制作用（IC50= 0.049–5.578 μM）。此外，化合物8f和8h在高浓度（10μM）下阻断NCI-H1975细胞中EGFR的自身磷酸化，并且通过稀释法证实化合物8f是不可逆抑制剂。重要的是，具有 C-6 脲连接侧链且不含 Michael 受体的化合物表现出中度至强的不可逆 EGFR 抑制作用。
A novel series of anilinoquinazoline compounds with C-6 urea-linked side chains was designed and synthesized as reversible inhibitors of epidermal growth factor receptor (EGFR) based on the structure–activity relationships (SARs) of anilinoquinazoline inhibitors. All compounds demonstrated good inhibition of EGFR wild type (EGFR wt) (IC50= 0.024–1.715 μM) and inhibited proliferation of A431cell line (IC50= 0.116–22.008 μM). The binding mode of compounds8a,8d,8kand8owas consistent with the biological results. Moreover, compounds8kand8lalmost completely blocked the phosphorylation of EGFR in A431 cell line at 0.01 μM. Interestingly, all of the compounds also demonstrated moderate inhibition of EGFR/T790M/L858R (IC50= 0.049–5.578 μM). In addition, compounds8fand8hblocked the autophosphorylation of EGFR in NCI-H1975 cells at high concentration (10 μM), and compound8fwas confirmed to be an irreversible inhibitor through the dilution method. Importantly, the compounds with C-6 urea-linked side chains which did not contain Michael acceptors demonstrated moderate to strong irreversible EGFR inhibition.