Werner (WRN) syndrome protein is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers. In this study, a series of new -arylquinazoline-4-amine analogs were designed and synthesized based on structure optimization of quinazoline. The structures of the thirty-two newly synthesized compounds were confirmed by H NMR, C NMR and ESI-MS. The anticancer activity against chronic myeloid leukemia cells (K562), non-small cell lung cancer cells (A549), human prostate cancer cells (PC3), and cervical cancer cells (HeLa) of the target compounds was evaluated. Among them, the inhibition ratio of compounds , , , and against four cancer cells at 5 μM concentration were more than 50 %. The IC values of compounds and were 0.3 ± 0.01 μM and 0.05 ± 0.02 μM in K562 cells respectively, compared with HeLa and A549 cells, and were more sensitive to K562 cells. In addition, the PC3 cells with WRN overexpression (PC3-WRN) was constructed, and and were more sensitive to PC3-WRN cells compared with the control group cells (PC3-NC). Then, the cell viability of the novel WRN inhibitors were further assessed by colony formation assay. Compared with PC3-NC cells, and had obvious inhibitory effect on PC3-WRN cell at 1000 nM. In summary, these results indicated that the compounds and could be WRN protein inhibitor with potent anticancer properties .

中文翻译：

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2-取代喹唑啉-4-胺衍生物的设计、合成及其抗肿瘤活性

Werner (WRN) 综合征蛋白是一种多功能酶，具有解旋酶、ATP 酶和核酸外切酶活性，这些活性对于人类细胞中许多 DNA 相关的活动是必需的。最近的研究确定 WRN 是癌症的合成致死靶点。本研究在喹唑啉结构优化的基础上，设计合成了一系列新型-芳基喹唑啉-4-胺类似物。 32个新合成的化合物的结构经1H NMR、13C NMR和ESI-MS确证。评价了目标化合物对慢性粒细胞白血病细胞（K562）、非小细胞肺癌细胞（A549）、人前列腺癌细胞（PC3）和宫颈癌细胞（HeLa）的抗癌活性。其中化合物 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 等化合物在5μM浓度下对四种癌细胞的抑制率均超过50%。化合物和化合物在K562细胞中的IC50值分别为0.3±0.01μM和0.05±0.02μM，与HeLa和A549细胞相比，对K562细胞更敏感。此外，构建了WRN过表达的PC3细胞（PC3-WRN），与对照组细胞（PC3-NC）相比，对PC3-WRN细胞更加敏感。然后，通过集落形成测定进一步评估新型 WRN 抑制剂的细胞活力。与PC3-NC细胞相比，1000 nM时对PC3-WRN细胞有明显的抑制作用。总之，这些结果表明该化合物可能是具有有效抗癌特性的WRN蛋白抑制剂。