Mohammed Eman R, Abdel Fattah Ezzat Manal, Seif Emad M, Essa Basma M, Abdel-Aziz Hatem A, Sakr Tamer M, Ibrahim Hany S
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, 11562 Cairo, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, 11562 Cairo, Egypt.
Bioorg Chem. 2024 Dec;153:107935. doi: 10.1016/j.bioorg.2024.107935. Epub 2024 Nov 2.
Breast cancer is the most common invasive cancer diagnosed in women, accounting for most cancer-related fatalities globally. Numerous investigations have revealed that breast cancer is characterized by abnormal expression and maintenance of EGFR levels. In terms of structural study and optimization of several EGFR inhibitors, two series of oxadiazole bearing imidazo[2,1-b]thiazole derivatives were designed and synthesized as potential EGFR inhibitors and assessed for their antitumor activity at NCI-USA. Four derivatives 3b, 3c, 3d and 3e elicited remarkable GI% against MDA-MB-468, T-47D and MCF-7 breast cancer cell lines. Thereafter, MTT assay was performed to reveal that compounds 3b (IC = 2.27 µM) and 3d (IC = 1.46 µM) showed promising cytotoxic activity against MCF-7 and MDA-MB-468 cell lines, respectively, compared to their reference drugs. Compounds 3b, 3d and 3e revealed good selectivity toward tumor cells with reasonable safety profile when tested against the normal cell line MCF-10a. In vitro EGFR inhibitory assay demonstrated that compounds 3b (IC = 0.099 µM) and 3d (IC = 0.086 µM) exhibited comparable inhibitory activity to the standard drug erlotinib (IC = 0.046 µM). A flow cytometric analysis demonstrated that derivatives 3b and 3d arrested the cell cycle at the S phase in MCF-7 and MDB-MB-468, respectively. Furthermore, the most active derivative 3d was subjected to in vivo radioactive studies. In-vivo biodistribution of Tc-3d complex showed a notable elevated accumulation in the targeted sarcoma muscle, indicating the targeting capacity of compound 3d in the tumor of sarcoma mice model. The binding mode of compounds 3b and 3d with EGFR was studied by molecular docking and was further inspected by molecular dynamic simulations. Both compounds were shown to be stable during the course of simulation and demonstrated a plausible interaction pattern with the EGFR binding pocket.
乳腺癌是女性中诊断出的最常见的浸润性癌症，在全球癌症相关死亡中占比最大。大量研究表明，乳腺癌的特征是表皮生长因子受体（EGFR）水平的异常表达和维持。在对几种EGFR抑制剂进行结构研究和优化方面，设计并合成了两个系列的含恶二唑的咪唑并[2,1-b]噻唑衍生物作为潜在的EGFR抑制剂，并在美国国立癌症研究所评估了它们的抗肿瘤活性。四种衍生物3b、3c、3d和3e对MDA-MB-468、T-47D和MCF-7乳腺癌细胞系表现出显著的生长抑制率（GI%）。此后，进行MTT试验以揭示化合物3b（IC₅₀ = 2.27 μM）和3d（IC₅₀ = 1.46 μM）分别对MCF-7和MDA-MB-468细胞系显示出有前景的细胞毒性活性，与它们的参考药物相比。当针对正常细胞系MCF-10a进行测试时，化合物3b、3d和3e对肿瘤细胞显示出良好的选择性且具有合理的安全性。体外EGFR抑制试验表明，化合物3b（IC₅₀ = 0.099 μM）和3d（IC₅₀ = 0.086 μM）表现出与标准药物厄洛替尼（IC₅₀ = 0.046 μM）相当的抑制活性。流式细胞术分析表明，衍生物3b和3d分别使MCF-7和MDB-MB-468细胞周期停滞在S期。此外，对活性最高的衍生物3d进行了体内放射性研究。Tc-3d复合物的体内生物分布显示在靶向的肉瘤肌肉中有显著升高的积累，表明化合物3d在肉瘤小鼠模型肿瘤中的靶向能力。通过分子对接研究了化合物3b和3d与EGFR的结合模式，并通过分子动力学模拟进一步检查。两种化合物在模拟过程中均显示稳定，并与EGFR结合口袋呈现出合理的相互作用模式。
