Synthesis, biological evaluation, and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors

Igor A. Schepetkin, Andrei I. Khlebnikov, Andrei S. Potapov, Anastasia R. Kovrizhina, Vladislava V. Matveevskaya, Maxim L. Belyanin, Dmitriy N. Atochin, Svitlana O. Zanoza, Nadiya M. Gaidarzhy, Sergiy A. Lyakhov, Liliya N. Kirpotina, Mark T. Quinn

Research output: Contribution to journalArticle

Abstract

c-Jun N-terminal kinases (JNKs) play a central role in many physiologic and pathologic processes. We synthesized novel 11H-indeno[1,2-b]quinoxalin-11-one oxime analogs and tryptanthrin-6-oxime (indolo(2,1-b)quinazoline-6,12-dion-6-oxime) and evaluated their effects on JNK activity. Several compounds exhibited sub-micromolar JNK binding affinity and were selective for JNK1/JNK3 versus JNK2. The most potent compounds were 10c (11H-indeno[1,2-b]quinoxalin-11-one O-(O-ethylcarboxymethyl) oxime) and tryptanthrin-6-oxime, which had dissociation constants (Kd) for JNK1 and JNK3 of 22 and 76 nM and 150 and 275 nM, respectively. Molecular modeling suggested a mode of binding interaction at the JNK catalytic site and that the selected oxime derivatives were potentially competitive JNK inhibitors. JNK binding activity of the compounds correlated with their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation in human monocytic THP-1Blue cells and interleukin-6 (IL-6) production by human MonoMac-6 cells. Thus, oximes with indenoquinoxaline and tryptanthrin nuclei can serve as specific small-molecule modulators for mechanistic studies of JNK, as well as potential leads for the development of anti-inflammatory drugs.

Original languageEnglish
Pages (from-to)179-191
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume161
DOIs
Publication statusPublished - 1 Jan 2019

Fingerprint

Quinoxalines
Molecular modeling
Oximes
JNK Mitogen-Activated Protein Kinases
Derivatives
Neurofibromin 1
Transcription Factor AP-1
Pathologic Processes
tryptanthrine
Modulators
Lipopolysaccharides
Interleukin-6
Catalytic Domain
Anti-Inflammatory Agents
Chemical activation
Molecules
Pharmaceutical Preparations

Keywords

  • 11H-indeno[1,2-b]quinoxalin-11-one
  • c-Jun N-Terminal kinase
  • Inflammation
  • Oxime
  • tropomyosin-related kinase
  • Tryptanthrin

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Synthesis, biological evaluation, and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors. / Schepetkin, Igor A.; Khlebnikov, Andrei I.; Potapov, Andrei S.; Kovrizhina, Anastasia R.; Matveevskaya, Vladislava V.; Belyanin, Maxim L.; Atochin, Dmitriy N.; Zanoza, Svitlana O.; Gaidarzhy, Nadiya M.; Lyakhov, Sergiy A.; Kirpotina, Liliya N.; Quinn, Mark T.

In: European Journal of Medicinal Chemistry, Vol. 161, 01.01.2019, p. 179-191.

Research output: Contribution to journalArticle

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abstract = "c-Jun N-terminal kinases (JNKs) play a central role in many physiologic and pathologic processes. We synthesized novel 11H-indeno[1,2-b]quinoxalin-11-one oxime analogs and tryptanthrin-6-oxime (indolo(2,1-b)quinazoline-6,12-dion-6-oxime) and evaluated their effects on JNK activity. Several compounds exhibited sub-micromolar JNK binding affinity and were selective for JNK1/JNK3 versus JNK2. The most potent compounds were 10c (11H-indeno[1,2-b]quinoxalin-11-one O-(O-ethylcarboxymethyl) oxime) and tryptanthrin-6-oxime, which had dissociation constants (Kd) for JNK1 and JNK3 of 22 and 76 nM and 150 and 275 nM, respectively. Molecular modeling suggested a mode of binding interaction at the JNK catalytic site and that the selected oxime derivatives were potentially competitive JNK inhibitors. JNK binding activity of the compounds correlated with their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation in human monocytic THP-1Blue cells and interleukin-6 (IL-6) production by human MonoMac-6 cells. Thus, oximes with indenoquinoxaline and tryptanthrin nuclei can serve as specific small-molecule modulators for mechanistic studies of JNK, as well as potential leads for the development of anti-inflammatory drugs.",
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AU - Potapov, Andrei S.

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AU - Matveevskaya, Vladislava V.

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