Dihydrotriazine derivatives display high anticancer activity and inducing apoptosis, ROS, and autophagy

• Published in: Bioorganic chemistry 2022-07, Vol.124, p.105813-105813, Article 105813
• Main Authors: Zhang, Tian-Yi, Bai, Xue-Qian, Zhou, Zhi-Jiang, Jin, Lian-Hai, Zhao, Dong-Hai, Sun, Si-Mei
• Format: Article
• Language: English
• Subjects: Anticancer agents; Autophagosomes; Dihydrotriazine derivatives; ROS levels
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105813

Series of dihydrotriazine derivatives bearing 5-aryloxypyrazole moieties were identified as novel anticancer agents. [Display omitted] •Compound 10e displayed better activity than commercial drugs (5-Fu), with an IC50 value of 2.12 µM for HepG-2 cells.•Compound 10e could enhance the expression of Cl-PARP, Cl-caspase-3 and Cl-caspase-9.•10e triggered the formation of autophagosomes by promoting the expression of LC3-II and Beclin-1. A series of dihydrotriazine derivatives bearing 5-aryloxypyrazole moieties were designed, and their anticancer activities against three human cancer cell lines (SGC-7901, HepG-2 and MCF-7) and one non-cancer cell line (LO2) were explored using the MTT assay in vitro. Most of the compounds exhibited potent antiproliferative activities against the three cancer cell lines, with compound 10e (IC50 = 2.12 µM) exhibiting the most potent antiproliferative activity against HepG-2 cells. Interestingly, autophagy was observed in the 10e-treated HepG-2 cells. Compound 10e also increased reactive oxygen species (ROS) levels and resulted in marked HepG-2 cells apoptosis. Further studies revealed that compound 10e could enhance the expression of Cl-PARP, Cl-caspase-3, and Cl-caspase-9. In addition, 10e triggered the formation of autophagosomes by promoting LC3-II and Beclin-1 expression. These results might be useful for exploring and developing dihydrotriazine derivatives as novel anticancer agents.