Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors; Frontiers in Pharmacology; Vol. 13

Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors; Frontiers in Pharmacology; Vol. 13

書誌詳細
Parent link:	Frontiers in Pharmacology Vol. 13.— 2022.— [958687, 14 p.]
団体著者:	Национальный исследовательский Томский политехнический университет Инженерная школа природных ресурсов Отделение химической инженерии
その他の著者:	Schepetkin (Shchepyotkin) I. A. Igor Aleksandrovich, Kovrizhina A. R. Anastasia Ruslanovna, Stankevich K. S. Ksenia Sergeevna, Khlebnikov A. I. Andrey Ivanovich, Kirpotina L. N. Liliya, Quinn M. T. Mark, Cook M. J. Matthew
要約:	Title screen 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 (Kd) and inhibition of cellular inflammatory responses (IC50). 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 (Kd = 340, 490, and 180 nM for JNK1, JNK2, and JNK3, respectively) and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcription activity in THP-1Blue cells and interleukin-6 (IL-6) production in MonoMac-6 monocytic cells (IC50 = 0.8 and 1.7 μM, respectively). Compound 1j also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1α, IL1β, 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 antiinflammatory drugs based on these nitrogen-containing heterocyclic systems
言語:	英語
出版事項:	2022
主題:	электронный ресурс труды учёных ТПУ anti-inflammatory 11H-indeno[1,2-b]quinoxalin-11-one interleukin-6 c-Jun N-terminal kinase nuclear factor-κB oxime tryptanthrin противовоспалительные средства интерлейкины оксимы триптофаны
オンライン･アクセス:	https://doi.org/10.3389/fphar.2022.958687
フォーマット:	電子媒体図書の章
KOHA link:	https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=668380

インターネット

https://doi.org/10.3389/fphar.2022.958687