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

• Published in: Molecules (Basel, Switzerland) Vol. 29; no. 8; p. 1779
• Main Authors: Hou, Xixi, Yan, Dong, Wu, Ziyuan, Mao, Longfei, Wang, Huili, Guo, Yajie, Yang, Jianxue
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.04.2024
• Subjects: 1,2,3-triazole; Acquired immune deficiency syndrome; AIDS; anti-tumor; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy - drug effects; Cancer; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; DNA; DNA damage; DNA Damage - drug effects; dolutegravir; Drug Discovery; Drug dosages; Drug resistance; Flow cytometry; Genetic aspects; Hep G2 Cells; hepatocellular carcinoma cell lines DNA damage; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; HIV; HIV (Viruses); Human immunodeficiency virus; Humans; Immune system; Liver cancer; Liver diseases; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Metabolism; Mortality; NMR; Nuclear magnetic resonance; Oxazines - chemistry; Oxazines - pharmacology; Piperazines - chemistry; Piperazines - pharmacology; Pyridones - chemistry; Pyridones - pharmacology; Raltegravir; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Toxicity; China; anti-tumor; hepatocellular carcinoma cell lines DNA damage; dolutegravir; 1,2,3-triazole
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29081779

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 and demonstrated exceptional efficacy, particularly against Huh7 cells, with IC 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 and activated the LC3 signaling pathway, inducing autophagy, and triggered the γ-H2AX signaling pathway, resulting in DNA damage in tumor cells. Compound exhibited low toxicity, highlighting its potential as a promising anti-tumor drug.