School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China; School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China; College of Pharmaceutical Science, Zhejiang Chinese Medical University, 310000, PR China.
Bioorg Chem. 2022 May;122:105747. doi: 10.1016/j.bioorg.2022.105747. Epub 2022 Mar 21.
Based on the structural skeleton of natural products boeravinones, two types of 6H-chromeno[3,4-b]quinoline derivatives were designed and synthesized by nitrogen atom substitution strategy. Then, their cytotoxic activities were evaluated against six human tumor cell lines including HepG2 (hepatocellular carcinoma), A2780 (ovarian cancer), Hela (cervical cancer), HCT116 (colorectal cancer), SW1990 (pancreatic cancer), and MCF7 (breast cancer). The results showed that compounds ZML-8 and ZML-14 exhibited robust inhibitory activities against HepG2 cells with IC values of 0.58 and 1.94 μM, respectively. In addition, ZML-8 and ZML-14 showed higher selectivity against HepG2 and L-02 cells than Topotecan. Mechanistically, ZML-8 and ZML-14 not only induced cell cycle arrest in the G2/M phase and cell apoptosis, but also dose-dependently inhibited topoisomerase I activity and induced DNA damage in HepG2 cells. Molecular docking showed that ZML-8 and ZML-14 could interact with topoisomerase I-DNA complex with a similar binding mode to Topotecan. Inhibitory activities of these two compounds on topoisomerase I were then confirmed in both cell-free systems and in whole-cell lysates. Taken together, compounds ZML-8 and ZML-14 merit further development as a new generation of non-camptothecin topoisomerase I inhibitors for the treatment of cancer.
基于天然产物 boeravinone 的结构骨架，采用氮原子取代策略设计并合成了两种 6H-色烯并[3,4-b]喹啉衍生物。然后，评估了它们对包括 HepG2（肝癌）、A2780（卵巢癌）、Hela（宫颈癌）、HCT116（结直肠癌）、SW1990（胰腺癌）和 MCF7（乳腺癌）在内的 6 个人类肿瘤细胞系的细胞毒性活性。结果表明，化合物 ZML-8 和 ZML-14 对 HepG2 细胞表现出强大的抑制活性，IC 值分别为 0.58 和 1.94μM。此外，ZML-8 和 ZML-14 对 HepG2 和 L-02 细胞的选择性高于拓扑替康。机制上，ZML-8 和 ZML-14 不仅诱导细胞周期停滞在 G2/M 期并诱导细胞凋亡，而且还剂量依赖性地抑制拓扑异构酶 I 活性并诱导 HepG2 细胞中的 DNA 损伤。分子对接表明，ZML-8 和 ZML-14 可以与拓扑异构酶 I-DNA 复合物以与拓扑替康相似的结合模式相互作用。随后在无细胞体系和全细胞裂解物中证实了这两种化合物对拓扑异构酶 I 的抑制活性。综上所述，化合物 ZML-8 和 ZML-14 作为新一代非喜树碱拓扑异构酶 I 抑制剂，值得进一步开发用于癌症治疗。
