Design and Synthesis of Novel Celastrol Derivatives as Potential Anticancer Agents against Gastric Cancer Cells.

Gastric cancer (GC) is a common malignant disease worldwide, and finding novel agents and strategies for the treatment of GC are of urgent need. Celastrol (CEL) is a well-known natural product with antineoplastic activity. In this study, pyrazole analogues were introduced at the C-29 position of CEL. A total of 24 new derivatives were designed, synthesized, and evaluated for their mechanism and antitumor activity in vitro and in vivo. Among them, compound exhibited the best activity against BGC-823 cells (IC = 0.21 ± 0.01 μM). Further biological studies showed that significantly raised the reactive oxygen species (ROS) levels to activate the apoptotic pathway, causing mitochondrial dysfunction in BGC-823 cells. In addition, also arrested cells in the G2/M phase to induce tumor cell apoptosis. In a nude mouse tumor xenograft model, exhibited a better tumor inhibition rate (89.85%) than CEL (inhibition rate 76.52%). Taken together, the present study has provided an anticancer lead compound candidate, , and has revealed that increased ROS generation may be an effective strategy in the treatment of GC.