Design, synthesis and antitumour activity evaluation of novel dolutegravir derivatives

Xi-Xi Hou; Long-Fei Mao; Yajie Guo; Chaoxuan Lou; Lan Wang; Rui-Fang Li; Huili Wang; San-Qiang Li; Jian-Xue Yang

doi:10.3389/fphar.2023.1238587

Design, synthesis and antitumour activity evaluation of novel dolutegravir derivatives

Front Pharmacol. 2023 Aug 7:14:1238587. doi: 10.3389/fphar.2023.1238587. eCollection 2023.

Authors

Xi-Xi Hou¹, Long-Fei Mao², Yajie Guo³, Chaoxuan Lou¹, Lan Wang², Rui-Fang Li², Huili Wang⁴, San-Qiang Li², Jian-Xue Yang¹

Affiliations

¹ Department of Pharmacy, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China.
² College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, China.
³ Department of Emergency, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
⁴ University of North Carolina Hospitals, Chapel Hill, NC, United States.

Abstract

Based on the modification of the structure of dolutegravir, we introduced 1,2,3-triazole moieties with different substituted groups and obtained a lot of novel dolutegravir derivatives. The activity of A549 cells treated with the derivatives was examined, and most compounds showed good inhibitory effects. Among them, compounds 4b and 4g were the most effective, and inhibited the growth of A549 cells with IC₅₀ values of 8.72 ± 0.11 μM and 12.97 ± 0.32 μM, respectively. In addition, compound 4g induced apoptosis and clonal suppression in A549 tumor cells. Compound 4g also activated the LC3 signaling pathway to induce autophagy in tumor cells, and activated the γ-H2AX signaling pathway to induce DNA damage in tumor cells.

Keywords: 1,2,3-triazole; DNA damage; antitumor; autophagy; dolutegravir.

Grants and funding

This work was supported by National Natural Science Foundation of China (82170606), Basic Research Project of Key Scientific Research Projects of Universities in Henan Province (23ZX006), Shenzhen Science and Technology Program (No. JCYJ20210324115208024), Shenzhen Outbound Postdoctoral Research Grant (No. CZBSHKYJJ002), The Key Scientific Research Projects of Universities in Henan Province (23B310001).