Synthesis and Evaluation of tetrahydroquinolin-2(1H)-one Derivatives as Novel Anti-Pancreatic Cancer Agents via Targeting Autophagy

摘要: Abstract Pancreatic cancer is one of the most deadly neoplasm with a 5-year survival rate less than 6% owing to its remarkable tolerance nutrient starvation, and new drugs treatment strategies are urgently needed. During project aiming at discovery anticancer agents, we performed structure modification on polycyclic polyprenylated acylphloroglucinols (PPAPs) skeleton, discovered that PPAP rearranged tetrahydroquinolin-2(1H)-one feature. Here, series derivatives were designed, synthesized evaluated against highly metastatic human pancreatic cell line (PANC-1), structure-activity relationship was also discussed. Among them, derivative 11k showed potent inhibitory activity an IC50 value 4.9 μM under nutrient-deprived condition. In contrast, all these exhibited low cytotoxicity PANC-1 cells normal condition, suggesting appeared allow alternative tumor death mechanisms, led toxicity. Further evaluations demonstrated decreased colony formation induced apoptosis PANC-1 condition in concentration dependent manner. in vivo study, significantly suppressed development weight nude mice. Preliminary mechanism research revealed clearly downregulated LC3-II expression increased level p62, two key autophagy markers critical signals for growth progression. Our current findings might be promising candidate chemotherapeutic molecule cancer, deserve further study.