Ugi Adducts as Novel Anti-austerity Agents against PANC-1 Human Pancreatic Cancer Cell Line: A Rapid Synthetic Approach.

Pancreatic cancer cells have an inherent tolerance to withstand nutrition starvation, allowing them to survive in hypovascular tumor microenvironments that lack of sufficient nutrients and oxygen. Developing anti-cancer agents that target this tolerance to nutritional starvation is a promising anti-austerity strategy for eradicating pancreatic cancer cells in their microenvironment. In this study, we employed a chemical biology approach using the Ugi reaction to rapidly synthesize new anti-austerity agents and evaluate their structure-activity relationships. Out of seventeen Ugi adducts tested, Ugi adduct 11 exhibited the strongest anti-austerity activity, showing preferential cytotoxicity against PANC-1 pancreatic cancer cells with a PC value of 0.5 µM. Further biological investigation of Ugi adduct 11 revealed a dramatic alteration of cellular morphology, leading to PANC-1 cell death within 24 h under nutrient-deprived conditions. Furthermore, the R absolute configuration of 11 was found to significantly contribute to the preferential anti-austerity ability toward PANC-1, with a PC value of 0.2 µM. Mechanistically, Ugi adduct (R)-11 was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway preferentially under nutrition starvation conditions. Consequently, Ugi-adduct (R)-11 could be a promising candidate for drug development targeting pancreatic cancer based on the anti-austerity strategy. Our study also demonstrated that the Ugi reaction-based chemical engineering of natural product extracts can be used as a rapid method for discovering novel anti-austerity agents for combating pancreatic cancer.