TY - JOUR

T1 - 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

AU - Schepetkin, Igor A.

AU - Khlebnikov, Andrei I.

AU - Potapov, Andrei S.

AU - Kovrizhina, Anastasia R.

AU - Matveevskaya, Vladislava V.

AU - Belyanin, Maxim L.

AU - Atochin, Dmitriy N.

AU - Zanoza, Svitlana O.

AU - Gaidarzhy, Nadiya M.

AU - Lyakhov, Sergiy A.

AU - Kirpotina, Liliya N.

AU - Quinn, Mark T.

N1 - Publisher Copyright: © 2018 Elsevier Masson SAS

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - 11H-indeno[1,2-b]quinoxalin-11-one

KW - c-Jun N-Terminal kinase

KW - Inflammation

KW - Oxime

KW - tropomyosin-related kinase

KW - Tryptanthrin

KW - Quinazolines/chemical synthesis

KW - Humans

KW - Models, Molecular

KW - Structure-Activity Relationship

KW - Oximes/chemical synthesis

KW - Protein Kinase Inhibitors/chemical synthesis

KW - Dose-Response Relationship, Drug

KW - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors

KW - Molecular Structure

UR - http://www.scopus.com/inward/record.url?scp=85055021473&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2018.10.023

DO - 10.1016/j.ejmech.2018.10.023

M3 - Article

C2 - 30347329

AN - SCOPUS:85055021473

VL - 161

SP - 179

EP - 191

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -