Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are commonly overexpressed in cancers making them appealing targets for cancer therapeutics. Two groups of indole-6-carboxylic acid derivatives, hydrazone derivatives targeting EGFR and oxadiazole derivatives targeting VEGFR-2, were synthesized and characterized using FT-IR, ¹H-NMR, ¹³CNMR, and HR-MS techniques. Binding patterns to potential molecular targets were studied using molecular docking and compared to standard EGFR and VEGFR-2 inhibitors. The newly synthesized compounds were cytotoxic to the three cancer cell lines tested (HCT-116, HeLa, and HT-29 cell lines) as evaluated by the MTT assay. Compound 3 b (EGFR-targeting) and compound 6 e (VEGFR-2-targeting) possessed the highest antiproliferation activity, were cancer-selective, arrested cancer cells in the G2/M phase, induced the extrinsic apoptosis pathway, and had the highest EGFR/VEGFR-2 enzyme inhibitory activity, respectively. The structure-activity relationships of the new compounds showed that the presence of an aryl or heteroaryl fragment attached to a linker is required for the anti-tumor activity. In conclusion, the findings of the current study suggest that compounds 3 b and 6 e are promising cytotoxic agents that act by inhibiting EGFR and VEGFR-2 tyrosine kinases, respectively.

中文翻译：

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作为多靶点抗增殖剂的新型吲哚 6 羧酸衍生物：合成、计算机研究和细胞毒性评估

表皮生长因子受体（EGFR）和血管内皮生长因子受体（VEGFR）通常在癌症中过度表达，这使得它们成为癌症治疗的有吸引力的靶点。合成了两组吲哚-6-羧酸衍生物，即靶向EGFR的腙衍生物和靶向VEGFR-2的恶二唑衍生物，并使用FT-IR、¹ H-NMR、¹³ CNMR和HR-MS技术进行表征。使用分子对接研究了与潜在分子靶标的结合模式，并与标准 EGFR 和 VEGFR-2 抑制剂进行了比较。通过 MTT 测定评估，新合成的化合物对测试的三种癌细胞系（HCT-116、HeLa 和 HT-29 细胞系）具有细胞毒性。化合物 3b（EGFR靶向）和化合物 6e（VEGFR-2靶向）具有最高的抗增殖活性，具有癌症选择性，将癌细胞阻滞在G2/M期，诱导外源性凋亡途径，并且具有最高的抗增殖活性。分别具有 EGFR/VEGFR-2 酶抑制活性。新化合物的结构-活性关系表明，连接基团上存在芳基或杂芳基片段是抗肿瘤活性所必需的。总之，当前研究的结果表明，化合物 3b和6e是有前途的细胞毒剂，分别通过抑制 EGFR 和 VEGFR-2 酪氨酸激酶发挥作用。