Zhong Hui, Zhao Mingxuan, Wu Chunyu, Zhang Jiayao, Chen Li, Sun Jianbo
State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
Eur J Med Chem. 2022 May 5;235:114300. doi: 10.1016/j.ejmech.2022.114300. Epub 2022 Mar 18.
A series of oxoisoaporphine derivatives with topoisomerase I inhibition and cytotoxic activities. Among them, compound 14 showed the most potent cytotoxic activity against all cancer cell lines tested, and substantially lower cytotoxicity to LO2 cells. Molecular docking studies, dynamics simulation and a follow-up enzyme inhibition assay indicated that 14 could interfere with DNA and significantly inhibit the activity of topoisomerase I. Further mechanistic studies revealed that 14 could arrest cell cycle at the G1 phase, and finally killed MCF-7 cells via apoptosis. In addition, 14 exhibited remarkable chemoreversal ability on multidrug-resistant MCF-7/ADR breast cancer cells. Some of its mechanisms may be related to inhibition of MCF-7/ADR P-gp-mediated Rhodamine (Rh123) efflux function and expression level, as well as inhibition of ROS, increase of ADR accumulation in MCF7/ADR cells, and enhancement of ADR in inducing apoptosis of MCF7/ADR cells. As 14 has little toxic and side effects, it may have the potential for further research.
一系列具有拓扑异构酶I抑制和细胞毒性活性的氧化异阿朴啡碱衍生物。其中，化合物14对所有测试的癌细胞系均表现出最强的细胞毒性活性，而对LO2细胞的细胞毒性则显著较低。分子对接研究、动力学模拟及后续的酶抑制试验表明，14可干扰DNA并显著抑制拓扑异构酶I的活性。进一步的机制研究表明，14可使细胞周期停滞于G1期，并最终通过凋亡杀死MCF-7细胞。此外，14对多药耐药的MCF-7/ADR乳腺癌细胞具有显著的化疗逆转能力。其部分机制可能与抑制MCF-7/ADR P-糖蛋白介导的罗丹明（Rh123）外排功能和表达水平、抑制活性氧、增加阿霉素在MCF7/ADR细胞中的蓄积以及增强阿霉素诱导MCF7/ADR细胞凋亡有关。由于14几乎没有毒副作用，它可能具有进一步研究的潜力。
