Author:
Hou Xixi,Mao Longfei,Guo Yajie,Wang Lan,Peng Lizeng,Wang Huili,Yang Jianxue,Li Sanqiang,Li Yue-Ming
Abstract
AbstractModification 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.
Funder
International Science and Technology Cooperation Project of Henan Province of China
Shenzhen Science and Technology Program
National Natural Science Foundation of China
Basic Research Project of Key Scientific Research Projects of Universities in Henan Province
2023 Henan Province Central guidance and local science and technology development fund support project
Publisher
Springer Science and Business Media LLC
Reference26 articles.
1. Siegel RL, Miller KD, Wagle NS. Jemal. Cancer statistics, 2023. CA-A Cancer J Clin. 2023;73(1):17–48.
2. Miller KD, Nogueira L, Devasia T, Mariotto AB, Yabroff KR, Jemal A, Kramer J, Siegel RL. Cancer Treat Survivorship Stat. 2022;72(5):409–36.
3. Biggar RJ, Chaturvedi AK, Goedert JJ, Engels EA. AIDS-Related cancer and severity of immunosuppression in persons with AIDS. J Natl Cancer Inst. 2007;99(12):962.
4. Piketty C, Selinger-Leneman H, Bouvier AM, Belot A, Mary-Krause M, Duvivier C, Bonmarchand M, Abramowitz L, Costagliola D, Grabar S. Incidence of HIV-Related anal Cancer remains increased despite long-term combined antiretroviral treatment: results from the French Hospital database on HIV. J Clin Oncol. 2012;30(35):4360.
5. Atallah-Yunes SA, Murphy DJ, Noy A. HIV-associated Burkitt lymphoma. Lancet Haematol. 2020;7(8):594.