# Synthesis and antitumor activity of dolutegravir derivatives bearing 1,2,3-triazole moieties

## TL;DR

Researchers modified the HIV drug dolutegravir to create new compounds that show strong anti-tumor effects in lung cancer cells.

## Contribution

The paper introduces new dolutegravir derivatives with 1,2,3-triazole moieties that exhibit potent anti-tumor activity.

## Key findings

- Compounds 9e and 9p showed strong anti-tumor activity in lung cancer cell lines with low IC50 values.
- These compounds induce cancer cell apoptosis and increase ROS levels, leading to cell death.
- Compound 9e has low toxicity to normal cells and shows promise for further development.

## Abstract

Modification of marketed drugs is an important way to develop drugs because its safety and clinical applicability. Oxygen-nitrogen heterocycles are a class of important active substances discovered in the process of new drug development. Dolutegravir, an HIV drug with a nitrogen-oxygen heterocycle structure, has the potential ability to inhibit cell survival. In order to find and explore novel anti-tumor drugs, new dolutegravir derivatives bearing different 1,2,3-triazole moieties were prepared via click reactions. In vitro biological experiments performed in several lung cancer cell lines suggested that these novel compounds displayed potent anti-tumor ability. Especially, the compound 9e with a substituent of 2-methyl-3-nitrophenyl and the compound 9p with a substituent of 3-trifluoromethylphenyl were effective against PC-9 cell line with IC50 values of 3.83 and 3.17 µM, respectively. Moreover, compounds 9e and 9p were effective against H460 and A549 cells. Further studies suggested that compounds 9e and 9p could induce cancer cell apoptosis in PC-9 and H460, inhibit cancer cell proliferation, change the cell cycle, and increase the level of reactive oxygen species (ROS) which further induce tumor cell apoptosis. In addition, compounds 9e and 9p increased LC3 protein expression which was the key regulator in autophagy signaling pathway in PC-9 cells. Compound 9e also showed low toxicity against normal cells, and could be regarded as an interesting lead compound for further structure optimization.