| RRC ID |
78564
|
| 著者 |
Tomohara K, Maneenet J, Ohashi N, Nose T, Fujii R, Kim MJ, Sun S, Awale S.
|
| タイトル |
Ugi Adducts as Novel Anti-austerity Agents against PANC-1 Human Pancreatic Cancer Cell Line: A Rapid Synthetic Approach.
|
| ジャーナル |
Biol Pharm Bull
|
| Abstract |
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.
|
| 巻・号 |
46(10)
|
| ページ |
1412-1420
|
| 公開日 |
2023-1-1
|
| DOI |
10.1248/bpb.b23-00224
|
| PMID |
37779042
|
| MeSH |
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Antineoplastic Agents, Phytogenic* / pharmacology
Cell Line, Tumor
Drug Screening Assays, Antitumor
Humans
Pancreatic Neoplasms* / drug therapy
Phosphatidylinositol 3-Kinases
Tumor Microenvironment
|
| リソース情報 |
| ヒト・動物細胞 |
PANC-1(RCB2095) |
