Аннотация:
c-Jun N-terminal kinase (JNK) plays a central role in stress signaling pathways implicated
in important pathological processes, including rheumatoid arthritis and ischemia-reperfusion injury.
Therefore, inhibition of JNK is of interest for molecular targeted therapy to treat various diseases. We
synthesized 13 derivatives of our reported JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime
and evaluated their binding to the three JNK isoforms and their biological effects. Eight compounds
exhibited submicromolar binding affinity for at least one JNK isoform. Most of these compounds also
inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1)
activation and interleukin-6 (IL-6) production in human monocytic THP1-Blue cells and human
MonoMac-6 cells, respectively. Selected compounds (4f and 4m) also inhibited LPS-induced cJun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. We conclude that
indenoquinoxaline-based oximes can serve as specific small-molecule modulators for mechanistic
studies of JNKs, as well as potential leads for the development of anti-inflammatory drugs.
