Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor.

c-Jun N-terminal kinases (JNKs) participate in many physiologic and pathologic processes, including inflammatory diseases. We recently synthesized the sodium salt of IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime) and demonstrated that it is a high-affinity JNK inhibitor and inhibits murine delayed-type hypersensitivity. Here we show that IQ-1S is highly specific for JNK and that its neutral form is the most abundant species at physiologic pH. Molecular docking of the IQ-1S syn isomer into the JNK1 binding site gave the best pose, which corresponded to the position of cocrystallized JNK inhibitor SP600125 (1,9-pyrazoloanthrone). Evaluation of the therapeutic potential of IQ-1S showed that it inhibited matrix metalloproteinase 1 and 3 gene expression induced by interleukin-1ß in human fibroblast-like synoviocytes and significantly attenuated development of murine collagen-induced arthritis (CIA). Treatment with IQ-1S either before or after induction of CIA resulted in decreased clinical scores, and joint sections from IQ-1S-treated CIA mice exhibited only mild signs of inflammation and minimal cartilage loss compared with those from control mice. Collagen II-specific antibody responses were also reduced by IQ-1S treatment. By contrast, the inactive ketone derivative 11H-indeno[1,2-b]quinoxalin-11-one had no effect on CIA clinical scores or collagen II-specific antibody titers. IQ-1S treatment also suppressed proinflammatory cytokine and chemokine levels in joints and lymph node cells. Finally, treatment with IQ-1S increased the number of Foxp3(+)CD4(+)CD25(+) regulatory T cells in lymph nodes. Thus, IQ-1S can reduce inflammation and cartilage loss associated with CIA and can serve as a small-molecule modulator for mechanistic studies of JNK function in rheumatoid arthritis.

Synthesis and biological activity of 7H-benzo[4,5]indolo[2,3-b]-quinoxaline derivatives.

New 7-(2-aminoethyl)-7H-benzo[4,5]indolo[2,3-b]quinoxalines (13-20) were synthesized with high yields starting from 3H-benzo[e]indole-1,2-dione. These compounds were screened for the cytotoxicity, anti-viral activity, interferon inducing ability and DNA affinity compared with the corresponding 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxaline derivatives (1-12). It was shown, that compounds 13-20 bind to DNA stronger (lg Кa=6.23-6.87) than compounds 1-12 (lg Кa=5.57-5.89). Anti-viral activity is significantly reduced with annulations of benzene ring in Indoloquinoxaline moiety 13-20.

Synthesis, cytotoxicity, antiviral activity and interferon inducing ability of 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines.

New 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines were synthesized with high yields using bromoethylisatin and 6-(2-bromoethyl)-6H-indolo[2,3-b]quinoxaline as intermediates. These compounds were screened for the cytotoxicity, antiviral activity and interferon inducing ability. It was shown, that tested 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines are low toxic potent interferon inducers and antivirals. Morpholine and 4-methyl-piperidine derivatives appeared as the most active antivirals and the least cytotoxic in the investigated series.

Synthesis and affinity to DNA of phenylbenzoimidazoles and benzoimidazo[1,2-c]quinazolines.

Novel N-(benzoimidazophenyl)dialkylaminoalkylamides and 6-dialkylaminoalkylbenzoimidazo[1,2-c]quinazolines were prepared as potential interferon inducers and antiviral agents. They were screened for the DNA affinity by the ethidium bromide displacement assay. It was shown that the lg K(a) values of the compounds containing tetracyclic benzoimidazo[1,2-c]quinazoline fragment are approximately one order magnitude greater than those of the corresponding acyclic phenylbenzoimidazole derivatives.