Design, synthesis and biological evaluation of novel ursolic acid derivatives as potent anti-pancreatic cancer agents.

Pancreatic cancer is a highly lethal malignancy with an urgent need for novel therapeutic strategies. Triterpenoids represent key scaffolds, with compelling anticancer potential, yet further structural optimization is required to enhance their efficacy. This study aimed to design, synthesize, and evaluate the anti-pancreatic cancer potency and drug-likeness of novel ursolic acid (UA) derivatives. Among these derivatives, the optimal compound MG9 significantly enhanced the anti-pancreatic cancer activity against CFPAC-1 (IC50: 1.66 ± 0.24 μM), PANC-1 (IC50: 2.21 ± 1.18 μM), MIA PaCa-2 (IC50: 2.79 ± 0.25 μM) and SW1990 (IC50: 3.73 ± 0.36 μM) in vitro. Mechanistic studies demonstrated that MG9 inhibited the survival, colony formation and G0/G1 cell-cycle arrest in CFPAC-1 cells. MG9 also induced ROS generation and mitochondrial mediated apoptosis in CFPAC-1 cells by upregulating p53, regulating Bax/Bcl-2, and releasing cytochrome C, highlighting α-hydroxyimination (MG9) derivative as promising candidate for pancreatic cancer therapy.