PMID- 36172181
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220930
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 13
DP  - 2022
TI  - Design, synthesis and biological evaluation of novel O-substituted tryptanthrin 
      oxime derivatives as c-Jun N-terminal kinase inhibitors.
PG  - 958687
LID - 10.3389/fphar.2022.958687 [doi]
LID - 958687
AB  - The c-Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that 
      regulate many physiological processes, including inflammatory responses, 
      morphogenesis, cell proliferation, differentiation, survival, and cell death. 
      Therefore, JNK represents an attractive target for therapeutic intervention. 
      Herein, a panel of novel tryptanthrin oxime analogs were synthesized and 
      evaluated for JNK1-3 binding (K(d)) and inhibition of cellular inflammatory 
      responses (IC(50)). Several compounds exhibited submicromolar JNK binding 
      affinity, with the most potent inhibitor being 
      6-(acetoxyimino)indolo[2,1-b]quinazolin-12(6H)-one (1j), which demonstrated high 
      JNK1-3 binding affinity (K(d) = 340, 490, and 180 nM for JNK1, JNK2, and JNK3, 
      respectively) and inhibited lipopolysaccharide (LPS)-induced nuclear 
      factor-kappaB/activating protein 1 (NF-kappaB/AP-1) transcription activity in THP-1Blue 
      cells and interleukin-6 (IL-6) production in MonoMac-6 monocytic cells (IC(50) = 
      0.8 and 1.7 muM, respectively). Compound 1j also inhibited LPS-induced production 
      of several other proinflammatory cytokines, including IL-1alpha, IL-1beta, 
      granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte 
      chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF) in MonoMac-6 
      cells. Likewise, 1j inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 
      cells, directly confirming JNK inhibition. Molecular modeling suggested modes of 
      binding interaction of selected compounds in the JNK3 catalytic site that were in 
      agreement with the experimental JNK3 binding data. Our results demonstrate the 
      potential for developing anti-inflammatory drugs based on these 
      nitrogen-containing heterocyclic systems.
CI  - Copyright (c) 2022 Schepetkin, Kovrizhina, Stankevich, Khlebnikov, Kirpotina, Quinn 
      and Cook.
FAU - Schepetkin, Igor A
AU  - Schepetkin IA
AD  - Department of Microbiology and Cell Biology, Montana State University, Bozeman, 
      MT, United States.
FAU - Kovrizhina, Anastasia R
AU  - Kovrizhina AR
AD  - Kizhner Research Center, Tomsk Polytechnic University, Tomsk, Russia.
FAU - Stankevich, Ksenia S
AU  - Stankevich KS
AD  - Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, 
      United States.
FAU - Khlebnikov, Andrei I
AU  - Khlebnikov AI
AD  - Kizhner Research Center, Tomsk Polytechnic University, Tomsk, Russia.
FAU - Kirpotina, Liliya N
AU  - Kirpotina LN
AD  - Department of Microbiology and Cell Biology, Montana State University, Bozeman, 
      MT, United States.
FAU - Quinn, Mark T
AU  - Quinn MT
AD  - Department of Microbiology and Cell Biology, Montana State University, Bozeman, 
      MT, United States.
FAU - Cook, Matthew J
AU  - Cook MJ
AD  - Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, 
      United States.
LA  - eng
PT  - Journal Article
DEP - 20220912
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC9510750
OTO - NOTNLM
OT  - 11H-indeno[1,2-b]quinoxalin-11-one
OT  - anti-inflammatory
OT  - c-Jun N-terminal kinase
OT  - interleukin-6
OT  - nuclear factor-kappaB
OT  - oxime
OT  - tryptanthrin
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/09/30 06:00
MHDA- 2022/09/30 06:01
PMCR- 2022/09/12
CRDT- 2022/09/29 02:13
PHST- 2022/05/31 00:00 [received]
PHST- 2022/08/22 00:00 [accepted]
PHST- 2022/09/29 02:13 [entrez]
PHST- 2022/09/30 06:00 [pubmed]
PHST- 2022/09/30 06:01 [medline]
PHST- 2022/09/12 00:00 [pmc-release]
AID - 958687 [pii]
AID - 10.3389/fphar.2022.958687 [doi]
PST - epublish
SO  - Front Pharmacol. 2022 Sep 12;13:958687. doi: 10.3389/fphar.2022.958687. 
      eCollection 2022.