Discovery of hydroxamate derivatives as potent anti-gastric cancer agents via inducing oxidative stress and DNA damage

Gastric cancer (GC) remains one of the most malignant cancers with high morbidity and mortality, necessitating the development of new agent for GC treatment. Herein, we evaluated the anti-proliferative activities of a series of hydroxamate derivatives 3a-3k against GC cells, and found that compound 3i could inhibit the proliferation of GC cells at micromolar level. The subsequent cell growth curve, cell morphology, cell cycle and cell apoptosis experiments indicated that compound 3i inhibited the growth of GC cells via inducing cell apoptosis rather than suppressing cell cycle. Besides, the rescue experiments showed that antioxidants (N-acetylcysteine and dithiothreitol) instead of cell apoptosis, necrosis or ferroptosis inhibitors could totally rescue the proliferation of GC cells prevented by compound 3i. Then, RNA-seq, western blotting and alkaline comet assay studies showed that compound 3i could cause DNA damage. Consistently, the in vivo experiments indicated that compound 3i could obviously inhibit the growth of tumor and induce the expression of p53 and γH2AX. Overall, compound 3i exhibited its anti-proliferative activity through increasing ROS level and inducing DNA damage, thus resulting in cell apoptosis of GC cells. Furthermore, docking study exposed the ability of compound 3i to chelate Zn²⁺ located within HDACs active site. Therefore, compound 3i provides an important strategy on developing lead compounds for GC therapy via oxidative stress.