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

文献类型： 外文期刊

作者： Hou, Xixi 1 ; Mao, Longfei 3 ; Guo, Yajie 6 ; Wang, Lan 3 ; Peng, Lizeng 7 ; Wang, Huili 8 ; Yang, Jianxue 1 ; Li, Sanqiang 3 ; Li, Yue-Ming 4 ;

作者机构： 1.Henan Univ Sci & Technol, Affiliated Hosp 1, Dept Pharm, Luoyang 471003, Peoples R China

2.Henan Univ Sci & Technol, Coll Clin Med, Luoyang 471003, Peoples R China

3.Henan Univ Sci & Technol, Coll Basic Med & Forens Med, Dept Pharmaceut Sci, 263 Kaiyuan Rd, Luoyang 471003, Peoples R China

4.Nankai Univ, Coll Pharm, State Key Lab Med Chem Biol, Haihe Educ Pk,38 Tongyan Rd, Tianjin 300350, Peoples R China

5.Nankai Univ, Tianjin Key Lab Mol Drug Res, Haihe Educ Pk,38 Tongyan Rd, Tianjin 300350, Peoples R China

6.Sun Yat Sen Univ, Affiliated Hosp 8, Dept Emergency, Shenzhen 518033, Peoples R China

7.Shandong Acad Agr Sci, Inst Agrofood Sci & Technol, Key Lab Agroprod Proc Technol Shandong Prov, Key Lab Novel Food Resources Proc,Minist Agr, Jinan 250100, Peoples R China

8.Univ North Carolina Hosp, 101 Manning Dr, Chapel Hill, NC 27599 USA

关键词： Dolutegravir; 1, 2, 3-triazole; Synthesis; Antitumor; Autophagy

期刊名称：BMC CHEMISTRY （ 影响因子：4.6； 五年影响因子：4.4 ）

ISSN：

年卷期： 2024 年 18 卷 1 期

页码：

收录情况： SCI

摘要： 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 mu M, 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.

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