Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad-500037, India.
Fluoro-Agrochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India.
Anticancer Agents Med Chem. 2019;19(16):1935-1948. doi: 10.2174/1871520619666190906162537.
The synthesis of novel heterocyclic scaffolds with amide functionality is a key research area due to their plethora of medicinal applications. The present study aims to explore the synthesis of new cinnamido linked quinazolinone congeners and their potential as anticancer agents.
Cytotoxicity evaluation, Cell cycle analysis, JC-1 staining, ROS, Annexin V assays, AO/EB, DAPI nuclear staining, Colony-forming assay and Western blot analysis.
Among the synthesized compounds, 5eb and 5fc have shown promising cytotoxic activity with an IC50 value of 3.89±1.01µM and 4.05±0.62µM against HeLa cell lines. The flow-cytometry analysis demonstrated that the compound 5eb arrested the sub-G1 phase of the cell cycle and induced apoptosis. Furthermore, the compound 5eb triggered the collapse of mitochondrial membrane potential (ΔΨm), which was assessed by JC-1 staining and also induced the generation of Reactive Oxygen Species. An increase in the expression of proapoptotic proteins such as Bax, p53, cleaved PARP and cleaved caspase-3 by 5eb confirmed the activation of the mitochondrial-dependent intrinsic apoptosis pathway.
Our results suggest that compound 5eb and 5fc of cinnamido linked quinazolinone derivatives could serve as potential leads in the development of novel chemotherapeutic agents.
具有酰胺官能团的新型杂环支架的合成是一个关键的研究领域，因为它们在医学应用方面有很多。本研究旨在探索新的肉桂酰基连接的喹唑啉酮同系物的合成及其作为抗癌剂的潜力。
细胞毒性评估、细胞周期分析、JC-1 染色、ROS、Annexin V 测定、AO/EB、DAPI 核染色、集落形成测定和 Western blot 分析。
在所合成的化合物中，化合物 5eb 和 5fc 对 HeLa 细胞系表现出有希望的细胞毒性，IC50 值分别为 3.89±1.01µM 和 4.05±0.62µM。流式细胞术分析表明，化合物 5eb 使细胞周期的亚 G1 期停滞并诱导细胞凋亡。此外，化合物 5eb 触发了线粒体膜电位（ΔΨm）的崩溃，这通过 JC-1 染色评估，并诱导活性氧（ROS）的产生。5eb 增加了促凋亡蛋白的表达，如 Bax、p53、cleaved PARP 和 cleaved caspase-3，证实了线粒体依赖性内在凋亡途径的激活。
我们的结果表明，肉桂酰基连接的喹唑啉酮衍生物的化合物 5eb 和 5fc 可能作为新型化疗药物开发的潜在先导化合物。
