2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2019 Jan 1:161:179-191. doi: 10.1016/j.ejmech.2018.10.023.
Igor A Schepetkin 1,  Andrei I Khlebnikov 2,  Andrei S Potapov 3,  Anastasia R Kovrizhina 3,  Vladislava V Matveevskaya 4,  Maxim L Belyanin 3,  Dmitriy N Atochin 5,  Svitlana O Zanoza 6,  Nadiya M Gaidarzhy 6,  Sergiy A Lyakhov 6,  Liliya N Kirpotina 1,  Mark T Quinn 7
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Montana State University, Bozeman, MT, 59717, USA.
  • 2 Kizhner Research Center, Tomsk Polytechnic University, Tomsk, 634050, Russia; Scientific Research Institute of Biological Medicine, Altai State University, Barnaul, 656049, Russia.
  • 3 Kizhner Research Center, Tomsk Polytechnic University, Tomsk, 634050, Russia.
  • 4 Kizhner Research Center, Tomsk Polytechnic University, Tomsk, 634050, Russia; Department of Chemistry, Siberian State Medical University, Tomsk, 634050, Russia.
  • 5 Kizhner Research Center, Tomsk Polytechnic University, Tomsk, 634050, Russia; Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
  • 6 A.V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, Odessa, Ukraine.
  • 7 Department of Microbiology and Immunology, Montana State University, Bozeman, MT, 59717, USA. Electronic address: mquinn@montana.edu.
PMID: 30347329 DOI: 10.1016/j.ejmech.2018.10.023
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.

Keywords

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

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