PMID- 37779042
OWN - NLM
STAT- MEDLINE
DCOM- 20231023
LR  - 20240102
IS  - 1347-5215 (Electronic)
IS  - 0918-6158 (Linking)
VI  - 46
IP  - 10
DP  - 2023
TI  - Ugi Adducts as Novel Anti-austerity Agents against PANC-1 Human Pancreatic Cancer 
      Cell Line: A Rapid Synthetic Approach.
PG  - 1412-1420
LID - 10.1248/bpb.b23-00224 [doi]
AB  - 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(50) value of 
      0.5 microM. 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(50) value of 0.2 microM. 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.
FAU - Tomohara, Keisuke
AU  - Tomohara K
AD  - Faculty of Arts and Science, Kyushu University.
FAU - Maneenet, Juthamart
AU  - Maneenet J
AD  - Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of 
      Toyama.
FAU - Ohashi, Nao
AU  - Ohashi N
AD  - Graduate School of Science, Kyushu University.
FAU - Nose, Takeru
AU  - Nose T
AD  - Faculty of Arts and Science, Kyushu University.
AD  - Graduate School of Science, Kyushu University.
FAU - Fujii, Rintaro
AU  - Fujii R
AD  - Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of 
      Toyama.
FAU - Kim, Min Jo
AU  - Kim MJ
AD  - Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of 
      Toyama.
FAU - Sun, Sijia
AU  - Sun S
AD  - Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of 
      Toyama.
FAU - Awale, Suresh
AU  - Awale S
AD  - Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of 
      Toyama.
LA  - eng
PT  - Journal Article
PL  - Japan
TA  - Biol Pharm Bull
JT  - Biological & pharmaceutical bulletin
JID - 9311984
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - 0 (Antineoplastic Agents)
SB  - IM
MH  - Humans
MH  - *Antineoplastic Agents, Phytogenic/pharmacology
MH  - Cell Line, Tumor
MH  - Phosphatidylinositol 3-Kinases
MH  - *Antineoplastic Agents/pharmacology/therapeutic use
MH  - *Pancreatic Neoplasms/drug therapy
MH  - Drug Screening Assays, Antitumor
MH  - Tumor Microenvironment
OTO - NOTNLM
OT  - Ugi reaction
OT  - anti-austerity agent
OT  - natural product hybrid
OT  - pancreatic cancer
OT  - preferential cytotoxicity
EDAT- 2023/10/02 00:41
MHDA- 2023/10/23 01:18
CRDT- 2023/10/01 22:14
PHST- 2023/10/23 01:18 [medline]
PHST- 2023/10/02 00:41 [pubmed]
PHST- 2023/10/01 22:14 [entrez]
AID - 10.1248/bpb.b23-00224 [doi]
PST - ppublish
SO  - Biol Pharm Bull. 2023;46(10):1412-1420. doi: 10.1248/bpb.b23-00224.