Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors

Abstract

The c-Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNK represents an attractive target for therapeutic intervention. Herein, a panel of novel tryptanthrin oxime analogs were synthesized and evaluated for JNK1-3 binding (Kd) and inhibition of cellular inflammatory responses (IC50). Several compounds exhibited submicromolar JNK binding affinity, with the most potent inhibitor being 6-(acetoxyimino)indolo[2,1-b]quinazolin-12(6H)-one (1j), which demonstrated high JNK1-3 binding affinity (Kd = 340, 490, and 180 nM for JNK1, JNK2, and JNK3, respectively) and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcription activity in THP-1Blue cells and interleukin-6 (IL-6) production in MonoMac-6 monocytic cells (IC50 = 0.8 and 1.7 μM, respectively). Compound 1j also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1α, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF) in MonoMac-6 cells. Likewise, 1j inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. Molecular modeling suggested modes of binding interaction of selected compounds in the JNK3 catalytic site that were in agreement with the experimental JNK3 binding data. Our results demonstrate the potential for developing anti-inflammatory drugs based on these nitrogen-containing heterocyclic systems.

Synthesis of Novel Oxime and Benzofuran Chemical Frameworks Possessing Potent Anticholinesterase Activity: A SAR Study Related to Alzheimer Disease

“…1 H NMR (500 MHz, CDCl 3 ) δ 8.48, s, 1H; 7.83, d (J = 1.93 Hz), 1H; 7.73, s, 1H; 7.59, t (J = 2.00 Hz), 1H; 7.52, dd (J = 8.77, 1.95 Hz), 1H; 7.42, m, 2H; 7.29, t (J = 8.10 Hz), 1H; 7.13, ddd (J = 7.99, 2.08, 1.02 Hz), 1H; 1.49, s, 9H. 13 41 and 42 in the file of supporting information.…”

“…1 H NMR (500 MHz, CDCl 3 ) δ 7.53, m, 2H; 7.40, ddd (J = 8.38, 7.20, 1.33 Hz), 1H; 7.30, m, 6H; 6.78, d (J = 0.92 Hz), 1H; 3.83, s, 2H; 1.42, s, 9H. 13 15 and 16 in the file of supporting information. (11) 17 and 18 in the file of supporting information.…”

“…(12): Yield: 0.85 g (94 %); m.p: 119 °C; FT-IR υ (cm 19 and 20 in the file of supporting information. (13): Yield: 0.65 g (94 %); m.p: 140 °C; FT-IR υ(cm À 1 , ATR): υ(CÀ H) 3173-3075 aromatic CÀ H stretching, υ(CÀ H) 2960-2865 aliphatic CÀ H stretching, υ(C=O) 1767 C=O stretching bands. 1 H NMR (500 MHz, CDCl 3 ) δ 8.52, dd (J = 4.85, 1.94 Hz), 1H; 8.00, dd (J = 7.71, 1.94 Hz), 1H; 7.76, d (J = 1.92 Hz), 1H; 7.47, dd (J = 8.76, 1.95 Hz), 1H; 7.41, d (J = 8.76 Hz), 1H; 7.31, dd (J = 7.71, 4.80 Hz), 1H; 7.16, d (J = 0.93 Hz), 1H; 1.43, s, 9H.…”

“…In the study realized by Schepetkin, Igor A et al., tryptanthrin oxime derivatives were synthesized and examined for JNK1–3 binding and inhibition of cellular inflammatory responses. According to the results, heterocyclic compounds bearing nitrogen atom (oximes) possess potential for discovering novel anti‐inflammatory drugs [13] . Synthesized triazoles and their oxime derivatives possess m‐PGES‐1 inhibitory activities which is a key target for the developing anticancer and anti‐inflammatory drug lead molecules [14] .…”

“…NMR spectra are given in Figure29and 30 in the file of supporting information. 9H 13. C NMR (126 MHz, CDCl 3 ) δ 159.00, 153.80, 151.60, 144.37, 136.48, 133.00, 130.70, 127.61, 127.26, 126.97, 123.64, 122.66, 121.13, 118.76, 117.01, 111.58, 39.11, 28.57.…”