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; European Journal of Medicinal Chemistry; Vol. 161
| Parent link: | European Journal of Medicinal Chemistry Vol. 161.— 2018.— [P. 179-191] |
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| Collectivité auteur: | |
| Autres auteurs: | , , , , , , , , , , , |
| Résumé: | Title screen 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-?B/activating protein 1 (NF-?B/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. Режим доступа: по договору с организацией-держателем ресурса |
| Langue: | anglais |
| Publié: |
2018
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| Sujets: | |
| Accès en ligne: | https://doi.org/10.1016/j.ejmech.2018.10.023 |
| Format: | MixedMaterials Électronique Chapitre de livre |
| KOHA link: | https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=658934 |
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| 200 | 1 | |a 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 |f I. A. Shchepyotkin, A. I. Khlebnikov, A. S. Potapov [et al.] | |
| 203 | |a Text |c electronic | ||
| 300 | |a Title screen | ||
| 320 | |a [References: 73 tit.] | ||
| 330 | |a 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-?B/activating protein 1 (NF-?B/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. | ||
| 333 | |a Режим доступа: по договору с организацией-держателем ресурса | ||
| 461 | 1 | |t European Journal of Medicinal Chemistry | |
| 463 | 1 | |t Vol. 161 |v [P. 179-191] |d 2018 | |
| 610 | 1 | |a электронный ресурс | |
| 610 | 1 | |a труды учёных ТПУ | |
| 610 | 1 | |a c-Jun N-Terminal kinase | |
| 610 | 1 | |a tryptanthrin | |
| 610 | 1 | |a 11H-indeno[1,2-b]quinoxalin-11-one | |
| 610 | 1 | |a Oxime | |
| 610 | 1 | |a tropomyosin-related kinase | |
| 610 | 1 | |a Inflammation | |
| 610 | 1 | |a киназы | |
| 610 | 1 | |a воспаление | |
| 701 | 1 | |a Shchepyotkin |b I. A. |c doctor-biophysicist |c leading researcher of Tomsk Polytechnic University, candidate of medical science |f 1962- |g Igor Aleksandrovich |3 (RuTPU)RU\TPU\pers\37358 | |
| 701 | 1 | |a Khlebnikov |b A. I. |c Chemist |c Professor of Tomsk Polytechnic University |f 1963- |g Andrey Ivanovich |3 (RuTPU)RU\TPU\pers\33927 |9 17500 | |
| 701 | 1 | |a Potapov |b A. S. |c Chemist |c Professor of Tomsk Polytechnic University, Doctor of chemical sciences |f 1981- |g Andrey Sergeevich |3 (RuTPU)RU\TPU\pers\33909 | |
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