Uncontrolled cell proliferation is a hallmark of cancer. The major regulator of the cell cycle, cyclin dependent kinase 2 (CDK2), has become a mature target for cancer treatment. Herein, we describe our efforts toward the discovery of a series of benzofuro[3,2-b]quinoline alkaloid derivatives as CDK2 inhibitors through a scaffold hopping strategy. Compound ZLHQ-5f has topoisomerase I (Topo I) inhibitory activity due to the unique structure of benzofurano[3,2-b]quinoline. Resultantly, ZLHQ-5f exhibited promising anti-proliferative and CDK2 inhibitory activities. It also arrests the cell cycle in S-phase, triggers apoptosis in HCT116 cells, and has a good safety profile in vivo. There has yet to be a report on dual CDK2/Topo I inhibitor, thus this will be a novel attempt.

不受控制的细胞增殖是癌症的标志。细胞周期的主要调节因子，细胞周期蛋白依赖性激酶 2 (CDK2)，已成为癌症治疗的成熟靶点。在这里，我们描述了我们通过支架跳跃策略发现一系列苯并呋喃[3,2- b ]喹啉生物碱衍生物作为 CDK2 抑制剂的努力。由于苯并呋喃[3,2- b ]喹啉的独特结构，化合物ZLHQ-5f具有拓扑异构酶I（Topo I）抑制活性。结果，ZLHQ-5f表现出有希望的抗增殖和 CDK2 抑制活性。它还能将细胞周期阻滞在 S 期，引发 HCT116 细胞凋亡，并在体内具有良好的安全性. 目前还没有关于CDK2/Topo I双重抑制剂的报道，因此这将是一个新的尝试。