School of Pharmaceutical Engineering, and Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
Bioorg Med Chem. 2022 Nov 15;74:117052. doi: 10.1016/j.bmc.2022.117052. Epub 2022 Oct 17.
Three types of 2-arylamino-4-(piperidin-4-yloxy)pyrimidines (I-III) were designed and synthesized as covalent EGFR(epidermal growth factor receptor) inhibitors by replacement of the common reported 4-(3-amino)phenoxyl moiety with 4-(4-hydroxy)piperidine-4-oxyl, and the introduction of fused-thiophene or -pyrrole on the pyrimidine core to strategically achieve conformational restriction. According to our biological evaluation, it was found that compound 9i could potently suppress EGFR kinase and H1975 cell proliferation, with IC values of 4.902 nM and 0.6210 μM, respectively. Further study showed that 9i not only demonstrated highly selective inhibitory effects toward EGFR over wild-type EGFR (EGFR), but it also had low cytotoxicity against normal HBE(human bronchial epithelial) and L-02 cells. Action mechanism studies showed that 9i effectively hindered cell migration and promoted apoptosis by AO(Acridine Orange)/EB(Ethidium Bromide) staining. These data would provide important clues for the screening of novel covalent EGFR inhibitors for non-small cell lung cancer (NSCLC) treatment.
三种 2-芳基-4-(哌啶-4-基氧基)嘧啶类化合物 (I-III) 被设计和合成，作为共价表皮生长因子受体 (EGFR) 抑制剂，通过用 4-(4-羟基)哌啶-4-氧取代常见报道的 4-(3-氨基)苯氧基部分，并在嘧啶核心上引入并噻吩或吡咯，以实现构象限制。根据我们的生物学评估，发现化合物 9i 能够有效地抑制 EGFR 激酶和 H1975 细胞的增殖，其 IC 值分别为 4.902 nM 和 0.6210 μM。进一步的研究表明，9i 不仅对野生型 EGFR (EGFR) 表现出高度选择性的抑制作用，而且对正常 HBE(人支气管上皮)和 L-02 细胞的细胞毒性也较低。作用机制研究表明，9i 通过 AO(吖啶橙)/EB(溴化乙锭)染色有效地阻碍细胞迁移并促进细胞凋亡。这些数据将为筛选新型共价 EGFR 抑制剂治疗非小细胞肺癌 (NSCLC) 提供重要线索。
