School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China.
School of Pharmacy, Xinxiang University, Xinxiang 453003, China.
Bioorg Chem. 2023 Mar;132:106385. doi: 10.1016/j.bioorg.2023.106385. Epub 2023 Jan 21.
In the current study, a series of novel quinolinedione-linked sulfonylpiperazine derivatives have been reported as NQO1-directed antitumor agents. A majority of compounds in this study were found to be more effective in resisting the proliferation of cancer cells than that of the positive control 5-Fu and TSA. Among the tested compounds, the derivative 22r exhibited considerable effect (IC, 3.29-5.19 µM) against the proliferation of three NQO1-rich cancer cells (HepG2, MCF-7, and A549), and was recognized to be an excellent NQO1 substrate as revealed by in vitro enzyme reduction assay and molecular docking study with NQO1. In studies on the mechanisms involved, 22r induced reactive oxygen species (ROS) production, caused DNA damage, and induced apoptosis in HepG2 cells. Remarkably, compound 22r exhibited excellent anticancer activity against HepG2 xenograft models in vivo. The study demonstrated that compound 22r provided a promising strategy for the management of malignant tumors.
在本研究中，我们报道了一系列新型喹喔啉二酮连接的磺酰基哌嗪衍生物，它们可作为 NQO1 导向的抗肿瘤剂。本研究中的大多数化合物在抵抗癌细胞增殖方面比阳性对照 5-Fu 和 TSA 更有效。在测试的化合物中，衍生物 22r 对三种 NQO1 丰富的癌细胞（HepG2、MCF-7 和 A549）的增殖具有相当大的作用（IC，3.29-5.19 μM），并且通过体外酶还原测定和与 NQO1 的分子对接研究被认为是一种极好的 NQO1 底物。在涉及的机制研究中，22r 诱导活性氧（ROS）的产生，导致 HepG2 细胞中的 DNA 损伤和细胞凋亡。值得注意的是，化合物 22r 在体内对 HepG2 异种移植模型表现出优异的抗癌活性。该研究表明，化合物 22r 为恶性肿瘤的治疗提供了一种有前途的策略。
