Nagineni Devendra, Murugesan Periyasamy, Abburi Naga Pranathi, Bollikanda Rakesh Kumar, Sridhar Balasubramanian, Tangutur Anjana Devi, Kantevari Srinivas
Fluro & Agrochemicals Division, CSIR- Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India; Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India.
Bioorg Chem. 2025 Mar;156:108208. doi: 10.1016/j.bioorg.2025.108208. Epub 2025 Jan 27.
A series of novel imidazole integrated substituted 1,2,4-oxadiazoles coupled with piperazines were synthesized from 5-chloro-4-(p-tolyl)-1H-imidazole-2-carbonitrile through a three-step synthetic pathway, resulting in excellent yields. All 26 hybrid imidazole derivatives were purified and characterized using NMR and HRMS techniques. Their cytotoxic effects were evaluated against five distinct cancer cell lines: MDA-MB-231 (breast), MIA PaCa-2 (pancreatic), DU-145 (prostate), HEP-G2 (liver), and HCT-116 (colorectal) utilizing the SRB assay. Compound 5w demonstrated the highest antiproliferative activity, with low IC values ranging from 7.51 ± 1.1 to 33.67 ± 1.4 µM across all evaluated cancer cell lines, whereas it exhibited less cytotoxicity in the normal human embryonic kidney epithelial cells (HEK-293T). Furthermore, compounds 5k, 5o, 5p, and 5q displayed selective cytotoxicity towards MDA-MB-231, while 5y showed anticancer activity exclusively in HEP-G2. Morphological assessments of 5w treated cell lines showed rounding of the cells and cell death. Flowcytometric cell cycle analysis revealed that 5w significantly increased the percentage of G2/M phase cells, indicating the G2/M cell cycle arrest in MDA-MB-231, MIA PaCa-2 and DU-145. Further, Western blot analysis strengthened that the potent compound 5w induced the G2/M cell cycle arrest, 5w treatment decreased the key cell cycle proteins CDK1, CDK2, and Cyclin B1 in a dose-dependent manner. Moreover, molecular docking studies indicated strong interactions between 5w and inhibitor of differentiation/DNA-binding proteins, highlighting its potential as a promising candidate for anticancer drug development.
通过三步合成途径，由5-氯-4-(对甲苯基)-1H-咪唑-2-腈合成了一系列新型的咪唑整合取代的1,2,4-恶二唑与哌嗪的偶联物，产率优异。所有26种杂化咪唑衍生物均通过核磁共振（NMR）和高分辨质谱（HRMS）技术进行了纯化和表征。利用SRB法评估了它们对五种不同癌细胞系的细胞毒性作用：MDA-MB-231（乳腺癌）、MIA PaCa-2（胰腺癌）、DU-145（前列腺癌）、HEP-G2（肝癌）和HCT-116（结直肠癌）。化合物5w表现出最高的抗增殖活性，在所有评估的癌细胞系中，其IC值较低，范围为7.51±1.1至33.67±1.4μM，而在正常人胚胎肾上皮细胞（HEK-293T）中表现出较低的细胞毒性。此外，化合物5k、5o、5p和5q对MDA-MB-231表现出选择性细胞毒性，而5y仅在HEP-G2中显示出抗癌活性。对用5w处理的细胞系进行的形态学评估显示细胞变圆并死亡。流式细胞术细胞周期分析表明，5w显著增加了G2/M期细胞的百分比，表明在MDA-MB-231、MIA PaCa-2和DU-145中出现G2/M期细胞周期阻滞。此外，蛋白质印迹分析进一步证实，强效化合物5w诱导G2/M期细胞周期阻滞，5w处理以剂量依赖性方式降低关键细胞周期蛋白CDK1、CDK2和细胞周期蛋白B1。此外，分子对接研究表明5w与分化/DNA结合蛋白抑制剂之间存在强相互作用，突出了其作为抗癌药物开发有前景候选物的潜力。
