Applied Biology Department, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana, 500007, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Apoptosis. 2022 Dec;27(11-12):825-839. doi: 10.1007/s10495-022-01745-w. Epub 2022 Jul 12.
Polyphenols are naturally occurring organic compounds with varying structures represented by four major groups: flavonoids, phenolic acids, lignans and stilbenes. Several studies suggested that these secondary metabolites have health benefits due to its anti-tumorigenic effect. Therefore, substantial effort has been put forward to isolate and characterize these natural compounds and synthesize analogues that may serve as potential anti-cancer therapeutics. This present study is aimed at designing and synthesis of azaflavanone derivative and in understanding its mechanism of action in vitro and in vivo. Molecular docking studies predicted that the compound can potentially bind strongly to the Cyclin E1-Cdk2 complex which is a key mediator of the cell cycle progression indicating a biological interference in aggressive prostate cancer. Further downstream studies to understand its cytotoxicity and mechanism of action showed this azaflavanone derivative markedly inhibits viability of prostate cancer cells (DU145) showing an IC value of 0.4 μM compared to other cancer cells. The pharmacological ROS insult using the azaflavanone derivative increases the oxidative damage leading to high expression of apoptotic markers with increasing concentration. On compound treatment, the cells lose the metabolic flexibility accompanied by mitochondrial dysfunction leading to cell cycle arrest and apoptosis. Further, no compound mediated toxicity was observed in xenograft mouse model of prostate cancer at a concentration as high as 5 mg/kg. The tumor burden was reduced to 60% rendering the azaflavanone derivative a potential candidate in cancer therapeutics. Collectively, the compound triggers cell cycle arrest and ROS mediated oxidative stress sensitizing the cancerous cells towards apoptosis.
多酚是具有不同结构的天然有机化合物，主要分为四大类：类黄酮、酚酸、木脂素和芪类。有几项研究表明，这些次级代谢产物具有抗癌作用，对健康有益。因此，人们投入了大量的精力来分离和鉴定这些天然化合物，并合成类似物，这些类似物可能成为潜在的抗癌治疗药物。本研究旨在设计和合成氮杂黄酮衍生物，并在体外和体内研究其作用机制。分子对接研究预测，该化合物可能与细胞周期进程的关键介质 Cyclin E1-Cdk2 复合物强烈结合，表明在侵袭性前列腺癌中存在生物学干扰。进一步的下游研究以了解其细胞毒性和作用机制表明，这种氮杂黄酮衍生物显著抑制前列腺癌细胞（DU145）的活力，IC 值为 0.4 μM，而对其他癌细胞则没有明显影响。使用氮杂黄酮衍生物进行药理学 ROS 损伤会导致氧化损伤增加，凋亡标志物的表达增加，浓度也随之增加。在化合物处理下，细胞失去代谢灵活性，伴随着线粒体功能障碍，导致细胞周期停滞和细胞凋亡。此外，在浓度高达 5mg/kg 的前列腺癌异种移植小鼠模型中，没有观察到化合物介导的毒性。肿瘤负担减少到 60%，使氮杂黄酮衍生物成为癌症治疗的潜在候选药物。综上所述，该化合物可引发细胞周期停滞和 ROS 介导的氧化应激，使癌细胞对凋亡敏感。
