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

Authors :
Xixi Hou
Dong Yan
Ziyuan Wu
Longfei Mao
Huili Wang
Yajie Guo
Jianxue Yang
Source :
Molecules, Vol 29, Iss 8, p 1779 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

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.

Details

Language :
English
ISSN :
14203049
Volume :
29
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.6ed4ca75a6ee4c5cbaabc879b27756ad
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules29081779