2. Academic Validation
  3. Design and synthesis of Aza-boeravinone derivatives as potential novel topoisomerase I inhibitors

Design and synthesis of Aza-boeravinone derivatives as potential novel topoisomerase I inhibitors

  • Bioorg Chem. 2022 May;122:105747. doi: 10.1016/j.bioorg.2022.105747.
Yong Zhou 1,  Yin-Peng Bai 2,  Mi Zhang 3,  Jian-Mei Gao 1,  Cheng-Jie Yang 4,  Zhi-Jun Zhang 5,  Nan Deng 6,  Lei Li 6,  Ying-Qian Liu 7,  Chuan-Rui Xu 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
  • 2 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.
  • 3 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.
  • 4 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China; College of Pharmaceutical Science, Zhejiang Chinese Medical University, 310000, PR China.
  • 5 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China. Electronic address: [email protected].
  • 6 School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
  • 7 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China; College of Pharmaceutical Science, Zhejiang Chinese Medical University, 310000, PR China. Electronic address: [email protected].
  • 8 School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China. Electronic address: [email protected].
PMID: 35338969 DOI: 10.1016/j.bioorg.2022.105747
Abstract

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 IC50 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.

Keywords

Anticancer; Boeravinone; Natural product; Synthesis; Topoisomerase I.

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