Dubey Rahul, Gupta Shankar, Singh Rajveer, Chandel Shivani, Thakur Shubham, Irani Mehdi, Gupta Ghanshyam Das, Asati Vivek
Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India.
Department of Pharmacognosy, ISF College of Pharmacy, Moga, Punjab, India.
Drug Dev Res. 2025 Sep;86(6):e70154. doi: 10.1002/ddr.70154.
The epidermal growth factor receptor (EGFR) is a common diver gene for lung cancer (NSCLC), which leads to an increasing death rate worldwide. This study reports the design, synthesis, and biological evaluation of triazole-clubbed pyrimidine derivatives (RDa-RDm) as potential anticancer agents. Thirteen compounds were synthesized and screened against the A549 lung cancer cell line. RDg emerged as the most potent derivative, exhibiting an IC of 15.70 µM, compared with the standard drug erlotinib (IC = 10.10 µM). Notably, all derivatives displayed moderate to excellent anticancer activity at 100 µM, with IC values ranging from 15.70 to 88.27 µM. RDg, characterised by a 4-chlorophenyl group, demonstrated strong in vitro activity and induced cell-cycle arrest at the sub-G0 phase. In vivo study using the Ehrlich ascites carcinoma (EAC) mouse model confirmed the superior anticancer efficacy of RDg. At a 5 mg/kg dose, RDg achieved a 52% reduction in tumour volume and 54% reduction in tumour weight compared with erlotinib 26% tumour volume reduction. Furthermore, RDg demonstrated a 90% tumour inhibition rate compared with erlotinib 75%, attributed to its enhanced cellular uptake and sustained release properties. In silico analyses provided insights into RDg mechanism of action, revealing strong interactions with EGFR binding sites, including hydrogen bonding with Met-793 and π-sulphur interaction with Met-790. Molecular dynamics simulations demonstrated RDg stabilising effect on EGFR, as evidenced by reduced protein flexibility and compact conformational space. The combination of promising in vitro, in vivo and in silico results showed RDg may be used as a lead compound for further development of novel compounds as EGFR inhibitors.
表皮生长因子受体（EGFR）是肺癌（非小细胞肺癌，NSCLC）中一种常见的驱动基因，这导致全球死亡率不断上升。本研究报告了作为潜在抗癌剂的三唑连接嘧啶衍生物（RDa - RDm）的设计、合成及生物学评价。合成了13种化合物并针对A549肺癌细胞系进行筛选。RDg成为最有效的衍生物，其IC50为15.70 μM，而标准药物厄洛替尼的IC50为10.10 μM。值得注意的是，所有衍生物在100 μM时均表现出中度至优异的抗癌活性，IC50值范围为15.70至88.27 μM。以4 - 氯苯基为特征的RDg表现出强大的体外活性，并诱导细胞周期停滞在亚G0期。使用艾氏腹水癌（EAC）小鼠模型进行的体内研究证实了RDg具有卓越的抗癌疗效。在5 mg/kg剂量下，与厄洛替尼使肿瘤体积减少26%相比，RDg使肿瘤体积减少52%，肿瘤重量减少54%。此外，与厄洛替尼的75%相比，RDg表现出90%的肿瘤抑制率，这归因于其增强的细胞摄取和缓释特性。计算机模拟分析深入了解了RDg的作用机制，揭示了与EGFR结合位点的强相互作用，包括与Met - 793的氢键和与Met - 790的π - 硫相互作用。分子动力学模拟证明了RDg对EGFR的稳定作用，表现为蛋白质灵活性降低和构象空间紧凑。体外、体内和计算机模拟的良好结果表明，RDg可作为进一步开发新型EGFR抑制剂化合物的先导化合物。
