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IQ-1 (11H-indeno[1,2-b]quinoxalin-11-one oxime) is a specific c-Jun N-terminal kinase (JNK) inhibitor with anticancer and neuro- and cardioprotective properties. Because aryloxime derivatives undergo cytochrome P450-catalyzed oxidation to nitric oxide (NO) and ketones in liver microsomes, NO formation may be an additional mechanism of IQ-1 pharmacological action. In the present study, electron paramagnetic resonance (EPR) of the Fe2+ complex with diethyldithiocarbamate (DETC) as a spin trap and hemoglobin (Hb) was used to detect NO formation from IQ-1 in the liver and blood of rats, respectively, after IQ-1 intraperitoneal administration (50 mg/kg). Introducing the spin trap and IQ-1 led to signal characteristics of the complex (DETC)2-Fe2+-NO in rat liver. Similarly, the introduction of the spin trap components and IQ-1 resulted in an increase in the Hb-NO signal for both the R- and the T-conformers in blood samples. The density functional theory (DFT) calculations were in accordance with the experimental data and indicated that the NO formation of IQ-1 through the action of superoxide anion radical is thermodynamically favorable. We conclude that the administration of IQ-1 releases NO during its oxidoreductive bioconversion in vivo. [ABSTRACT FROM AUTHOR]

Ericameria nauseosa (Pall. ex Pursh) G.L. Nesom & G.I. Baird) is used in traditional medicine to treat various diseases; however, little is known about the immunomodulatory activity of essential oil from this plant. Thus, we isolated essential oil from the aerial parts of E. nauseosa and evaluated their chemical composition and biological activity. Compositional analysis of E. nauseosa essential oil revealed that the main (>2%) components were γ-decalactone (13.3%), cryptone (9.4%), terpinen-4-ol (9.3%), (E)-methyl cinnamate (6.0%), T-cadinol (4.7%), spathulenol (3.6%), 8Z-2,3-dihydromatricaria ester (3.1%), β-phellandrene (3.0%), p-cymen-8-ol (2.2%), 3-ethoxy-2-cycloocten-1-one (2.2%), and trans-p-menth-2-en-1-ol (2.1%). Distinctive features were the lactones (up to 15%) and polyacetylenes (up to 3.1%), including (2Z,8Z)-matricaria ester and 8Z-2,3-dihydromatricaria ester. A comparison with other reported E. nauseosa essential oil samples showed that our samples were distinct from those collected in other areas of the country; however, they did have the most similarity to one sample collected in North Central Utah. Pharmacological studies showed that E. nauseosa essential oil activated human neutrophil Ca2+ influx, which desensitized these cells to subsequent agonist-induced functional responses. Based on our previously reported data that nerolidol, β-pinene, spathulenol, sabinene, and γ-terpinene were active in human neutrophils, these compounds are the most likely constituents contributing to this immunomodulatory activity. However, the relatively high amount of polyacetylenes may also contribute, as these compounds have been characterized as potent immunomodulators. [ABSTRACT FROM AUTHOR]

N‐formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a dual role in the progression/suppression of some cancers. Therefore, FPRs represent an important therapeutic target for the treatment of both cancer and inflammatory diseases. Previously, we identified selective or mixed FPR agonists with pyridazinone or pyridinone scaffolds showing a common 4‐(bromophenyl)acetamide fragment, which was essential for activity. We report here new pyrazole and pyrazolone derivatives as restricted analogues of the above 6‐membered compounds, all exhibiting the same 4‐bromophenylacetamide side chain. Most new products had low or absent FPR agonist activity, suggesting that the pyrazole nucleus was not appropriate for FPR agonists. This hypothesis was confirmed by molecular modeling studies, which highlighted that the five‐membered scaffold was responsible for a worse arrangement of the molecules in the receptor binding site. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Grindelia squarrosa (Pursh) Dunal is used in traditional medicine for treating various diseases; however, little is known about the immunomodulatory activity of essential oils from this plant. Thus, we isolated essential oils from the flowers (GEO Fl ) and leaves (GEO Lv ) of G. squarrosa and evaluated the chemical composition and innate immunomodulatory activity of these essential oils. Compositional analysis of these essential oils revealed that the main components were α-pinene (24.7 and 23.2% in GEO Fl and GEO Lv , respectively), limonene (10.0 and 14.7%), borneol (23.4 and 16.6%), p -cymen-8-ol (6.1 and 5.8%), β-pinene (4.0 and 3.8%), bornyl acetate (3.0 and 5.1%), trans -pinocarveol (4.2 and 3.7%), spathulenol (3.0 and 2.0%), myrtenol (2.5 and 1.7%), and terpinolene (1.7 and 2.0%). Enantiomer analysis showed that α-pinene, β-pinene, and borneol were present primarily as (-)-enantiomers (100% enantiomeric excess (ee) for (-)-α-pinene and (-)-borneol in both GEO Fl and GEO Lv ; 82 and 78% ee for (-)-β-pinene in GEO Fl and GEO Lv ), while limonene was present primarily as the (+)-enantiomer (94 and 96 ee in GEO Fl and GEO Lv ). Grindelia essential oils activated human neutrophils, resulting in increased [Ca 2+ ] i (EC 50 = 22.3 µg/mL for GEO Fl and 19.4 µg/mL for GEO Lv ). In addition, one of the major enantiomeric components, (-)-borneol, activated human neutrophil [Ca 2+ ] i (EC 50 = 28.7 ± 2.6), whereas (+)-borneol was inactive. Since these treatments activated neutrophils, we also evaluated if they were able to down-regulate neutrophil responses to subsequent agonist activation and found that treatment with Grindelia essential oils inhibited activation of these cells by the N -formyl peptide receptor 1 (FPR1) agonist f MLF and the FPR2 agonist WKYMVM. Likewise, (-)-borneol inhibited FPR-agonist-induced Ca 2+ influx in neutrophils. Grindelia leaf and flower essential oils, as well as (-)-borneol, also inhibited f MLF-induced chemotaxis of human neutrophils (IC 50 = 4.1 ± 0.8 µg/mL, 5.0 ± 1.6 µg/mL, and 5.8 ± 1.4 µM, respectively). Thus, we identified (-)-borneol as a novel modulator of human neutrophil function.