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

doi:10.1016/j.ejmech.2018.10.023

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. Epub 2018 Oct 12.

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.

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 (K_d) 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.

MeSH terms

Dose-Response Relationship, Drug
Humans
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
JNK Mitogen-Activated Protein Kinases / metabolism
Models, Molecular
Molecular Structure
Oximes / chemical synthesis
Oximes / chemistry
Oximes / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Structure-Activity Relationship

Substances

Oximes
Protein Kinase Inhibitors
Quinazolines
tryptanthrin-6-oxime
11H-pyrido(2,1-b)quinazolin-11-one
JNK Mitogen-Activated Protein Kinases

Grants and funding

P30 GM110732/GM/NIGMS NIH HHS/United States