Design and synthesis of cabotegravir derivatives bearing 1,2,3-triazole and evaluation of anti-liver cancer activity

Huaxia Xie; Longfei Mao; Gaolu Fan; Ziyuan Wu; Yimian Wang; Xixi Hou; Jiangang Wang; Huili Wang; Ling Liu; Sanqiang Li

doi:10.3389/fphar.2023.1265289

Design and synthesis of cabotegravir derivatives bearing 1,2,3-triazole and evaluation of anti-liver cancer activity

Front Pharmacol. 2023 Oct 6:14:1265289. doi: 10.3389/fphar.2023.1265289. eCollection 2023.

Authors

Huaxia Xie^#¹, Longfei Mao^#¹, Gaolu Fan², Ziyuan Wu¹, Yimian Wang¹, Xixi Hou³, Jiangang Wang¹, Huili Wang⁴, Ling Liu¹, Sanqiang Li¹

Affiliations

¹ College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, China.
² Department of Pharmacy, Luoyang Third People's Hospital, Luoyang, China.
³ Department of Pharmacy, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China.
⁴ University of North Carolina Hospitals, Chapel Hill, NC, United States.

^# Contributed equally.

Abstract

Based on the structure of the anti-HIV drug cabotegravir, we introduced 1,2,3-triazole groups with different substituents to obtain 19 cabotegravir derivatives and tested their activity against HepG2 cells. The proliferation of HepG2 cells was examined following treatment with derivatives. Most of the compounds demonstrated significant inhibitory effects, particularly compounds KJ-5 and KJ-12 with IC₅₀ values of 4.29 ± 0.10 and 4.07 ± 0.09 μM, respectively. Furthermore, both compounds 5 and 12 significantly caused cell apoptosis, G2/M arrest, and DNA damage, and suppressed invasion and migration in a concentration-dependent manner. In addition, KJ-5 and KJ-12 could trigger apoptosis via the mitochondrial pathway by increasing the ratio of Bax/Bcl-2 and activating cleaved caspase-9, cleaved caspase-3, and cleaved PARP.

Keywords: 1,2,3-triazole; apoptosis; cabotegravir; derivatives; invasion.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (82170606) and the Basic Research Project of Key Scientific Research Projects of Universities in Henan Province (23ZX006).