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

• Published in: Biological & pharmaceutical bulletin Vol. 46; no. 10; pp. 1412 - 1420
• Main Authors: Tomohara, Keisuke, Maneenet, Juthamart, Ohashi, Nao, Nose, Takeru, Fujii, Rintaro, Kim, Min Jo, Sun, Sijia, Awale, Suresh
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-10-2023; Japan Science and Technology Agency
• Subjects: 1-Phosphatidylinositol 3-kinase; Absolute configuration; Adducts; AKT protein; anti-austerity agent; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Agents, Phytogenic - pharmacology; Antitumor agents; Cell death; Cell Line, Tumor; Cytology; Cytotoxicity; Drug development; Drug Screening Assays, Antitumor; Humans; Kinases; natural product hybrid; Natural products; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Phosphatidylinositol 3-Kinases; preferential cytotoxicity; Rapamycin; Signal transduction; TOR protein; Tumor Microenvironment; Ugi reaction; preferential cytotoxicity; pancreatic cancer; natural product hybrid; Ugi reaction; anti-austerity agent
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b23-00224

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 PC50 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 PC50 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.