6- AND 7-AMINOMETHYL-11H-INDENO[1,2-b]QUINOXALINE-11-ONES – SYNTHESIS, DNA AFINITY AND TOXICITY

Duma, H. I.; Sazonov, K. D.; Liakhov, L. S.; Toporov, S. V.; Ляхов, С. А.

doi:10.18524/2304-0947.2020.1(73).198316

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“…There was no reason to assume that the corresponding oxime differed in isomeric composition, so the real affinity of the active isomer may be 1.5-3 times higher than that which we found. been reported previously to be a potential antiviral agent and DNA intercalator [51]. Simultaneous substitution at R 3 (Br or CF3) and R 1 (CH3, CF3, Cl, or Br) led to inactive compounds 4c, 4h, 4i, and 4j for all JNK.…”

Section: Binding Affinity Of Novel Compounds Toward Jnk1-3mentioning

confidence: 83%

“…To increase their bioavailability for potential pharmaceutical applications, it will be necessary to apply special techniques (e.g., see [ 50 ]). Note that 4m has been reported previously to be a potential antiviral agent and DNA intercalator [ 51 ] . Simultaneous substitution at R 3 (Br or CF 3 ) and R 1 (CH 3 , CF 3 , Cl, or Br) led to inactive compounds 4c, 4h, 4i, and 4j for all JNK.…”

Section: Resultsmentioning

confidence: 99%

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Novel c-Jun N-Terminal Kinase (JNK) Inhibitors with an 11H-Indeno[1,2-b]quinoxalin-11-one Scaffold

et al. 2021

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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 c-Jun 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.

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Section: Binding Affinity Of Novel Compounds Toward Jnk1-3mentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%