DataSheet1_Pyrazolyl-s-triazine with indole motif as a novel of epidermal growth factor receptor/cyclin-dependent kinase 2 dual inhibitors.docx

A series of pyrazolyl-s-triazine compounds with an indole motif was designed, synthesized, and evaluated for anticancer activity targeting dual EGFR and CDK-2 inhibitors. The compounds were tested for cytotoxicity using the MTT assay. Compounds 3h, 3i, and 3j showed promising cytotoxic activity against two cancer cell lines, namely A549, MCF-7, and HDFs (non-cancerous human dermal fibroblasts). Compound 3j was the most active candidate against A549, with an IC50 of 2.32 ± 0.21 μM. Compounds 3h and 3i were found to be the most active hybrids against MCF-7 and HDFs, with an IC50 of 2.66 ± 0.26 μM and 3.78 ± 0.55 μM, respectively. Interestingly, 3i showed potent EGFR inhibition, with an IC50 of 34.1 nM compared to Erlotinib (IC50 = 67.3 nM). At 10 μM, this candidate caused 93.6% and 91.4% of EGFR and CDK-2 inhibition, respectively. Furthermore, 3i enhanced total lung cancer cell apoptosis 71.6-fold (43.7% compared to 0.61% for the control). Given the potent cytotoxicity exerted by 3i through apoptosis-mediated activity, this compound emerges as a promising target-oriented anticancer agent.

本研究设计并合成了一系列带有吲哚母核（indole motif）的吡唑基-s-三嗪类化合物，并针对双靶点表皮生长因子受体（EGFR）与细胞周期蛋白依赖性激酶2（CDK-2）开展抗癌活性评价。研究采用MTT法（MTT assay）对上述化合物进行细胞毒性测试。结果显示，化合物3h、3i与3j对A549、MCF-7两种癌细胞系以及非癌性人真皮成纤维细胞（HDFs，non-cancerous human dermal fibroblasts）均展现出良好的细胞毒活性。其中，化合物3j对A549细胞的抑制活性最为突出，其半数抑制浓度（IC50）为2.32 ± 0.21 μM。化合物3h与3i则分别对MCF-7和HDFs展现出最优的杂合分子活性，对应的IC50值分别为2.66 ± 0.26 μM与3.78 ± 0.55 μM。值得注意的是，化合物3i对EGFR的抑制活性极强，IC50达34.1 nM，优于对照药厄洛替尼（Erlotinib，IC50 = 67.3 nM）。在10 μM浓度下，该候选化合物对EGFR与CDK-2的抑制率分别达到93.6%与91.4%。此外，化合物3i可使肺癌细胞的总凋亡率提升71.6倍（实验组凋亡率为43.7%，对照组仅为0.61%）。鉴于化合物3i可通过介导细胞凋亡发挥强效细胞毒性，该化合物有望成为一款极具潜力的靶点导向型抗癌候选药物。