Discovery of Dolutegravir Derivative against Liver Cancer via Inducing Autophagy and DNA Damage

Molecules. 2024 Apr 13;29(8):1779. doi: 10.3390/molecules29081779.

Abstract

We introduced a terminal alkyne into the core structure of dolutegravir, resulting in the synthesis of 34 novel dolutegravir-1,2,3-triazole compounds through click chemistry. These compounds exhibited remarkable inhibitory activities against two hepatocellular carcinoma cell lines, Huh7 and HepG2. Notably, compounds 5e and 5p demonstrated exceptional efficacy, particularly against Huh7 cells, with IC50 values of 2.64 and 5.42 μM. Additionally, both compounds induced apoptosis in Huh7 cells, suppressed tumor cell clone formation, and elevated reactive oxygen species (ROS) levels, further promoting tumor cell apoptosis. Furthermore, compounds 5e and 5p activated the LC3 signaling pathway, inducing autophagy, and triggered the γ-H2AX signaling pathway, resulting in DNA damage in tumor cells. Compound 5e exhibited low toxicity, highlighting its potential as a promising anti-tumor drug.

Keywords: 1,2,3-triazole; anti-tumor; dolutegravir; hepatocellular carcinoma cell lines DNA damage.

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Apoptosis* / drug effects
  • Autophagy* / drug effects
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Damage* / drug effects
  • Drug Discovery
  • Hep G2 Cells
  • Heterocyclic Compounds, 3-Ring* / chemistry
  • Heterocyclic Compounds, 3-Ring* / pharmacology
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Oxazines* / chemistry
  • Oxazines* / pharmacology
  • Piperazines* / chemistry
  • Piperazines* / pharmacology
  • Pyridones* / chemistry
  • Pyridones* / pharmacology
  • Reactive Oxygen Species* / metabolism
  • Signal Transduction / drug effects

Substances

  • Pyridones
  • dolutegravir
  • Piperazines
  • Oxazines
  • Heterocyclic Compounds, 3-Ring
  • Antineoplastic Agents
  • Reactive Oxygen Species

Grants and funding

This work was supported by The International Science and Technology Cooperation Project of Henan Province of China (242102520016). 2023 Henan Province Central guidance and local science and technology development fund support project(Z20231811030), The Key Scientific Research Projects of Universities in Henan Province (24A350006), The Henan Province Medical Science and Technology Research Project (LHGJ20230450), and The College Students’ Innovative Entrepreneurial Training Plan Program (202310464081).