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. et al.
In: European Journal of Medicinal Chemistry, Vol. 161, 01.01.2019, p. 179-191.Research output: Contribution to journal › Article › peer-review
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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 -
ID: 25397915