One-pot synthesis of 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinates and arylmethylene-bis-3,3-quinoline-2-ones

In this investigation an efficient synthesis of 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinic acid derivatives was achieved by one-pot reaction of one equivalent of aromatic amines with two equivalents of diethyl malonate in diphenyl ether and catalyzed with triethylamine. In case of applying the previous condition with aromatic amines and diethyl malonate in a ratio of 2:1, no quinolone structure was obtained, whereas N-1,N-3-bis(4-bromophenyl)malonamide, as an example, was obtained in 95% yield. Under the same previous condition, arylmethylene-bis-3,3-quinoline-2-ones were in one pot synthesized via the reaction of equal equivalents of aromatic amines and diethyl malonate together with half equivalent of the corresponding aromatic aldehydes. The structure of the obtained compounds was proved by IR, NMR and mass spectra and X-ray structure analyses. [GRAPHICS] .Peer reviewe

QT interval and dispersion among emergency medical responders in Mansoura city

AbstractBackgroundOccupational factors are likely to contribute to increased cardiovascular disease risk among emergency medical responders (EMR). The aim of this study was to clarify whether EMR stressful Job and their prolonged exposure to work stress are associated with an increase in QT interval and QT dispersion.MethodsA comparative cross sectional study was conducted upon 137 EMR and a 119 matched control group composed of non-emergency workers. All study population were subjected to history taking for age, risk factors such as diabetes mellitus, hypertension, and smoking, history of cardiovascular disease, and the use of medications. Measurement of blood pressure, and body mass index (BMI) was recorded. Standard 12-lead ECGs were recorded for the analysis of heart rate (HR), QT, QTc, QT dispersion, Tpeak and Tend (Tpe), and Tpe dispersion. In addition the levels of epinephrine and nor-epinephrine hormones in urine during the work shift were analyzed.ResultsHigh risk EMR had a significant increase in blood pressure, urinary epinephrine and norepinephrine compared to the control group (p<0.05). There were no differences between studied groups as regards heart rate, QT, QTc, QT dispersion, QTc dispersion, Tpe interval, and Tpe dispersion with no significant correlation between catecholamine levels and QTc interval.ConclusionQTc and dispersion were not increased among emergency medical responders in spite of having higher catecholamine levels

Synthesis of spiro[indoline-3,4'-pyrano[3,2-c]quinolone]-3'-carbonitriles

Quinoline-2,4-diones reacted with 2-(2-oxo-1,2-dihydroindol-3-ylidene)malononitrile in pyridine to give 2'-amino-2,5'-dioxo-5',6'-dihydrospiro(indoline-3,4'-pyrano[3,2-c]quinoline)-3'-carbonitriles in good to excellent yields. The structures of all new products were proven using one- and two-dimensional NMR, IR, and mass spectral data, and in five cases X-ray structural analyses. The possible mechanism for the reaction is also discussed. [GRAPHICS] .Peer reviewe

Design and synthesis of (2-oxo-1,2-dihydroquinolin-4-yl)-1,2,3-triazole derivatives via click reaction: Potential apoptotic antiproliferative agents

A mild and versatile method based on Cu-catalyzed [2+3] cycloaddition (Huisgen-Meldal-Sharpless reaction) was developed to tether 3,3’-((4-(prop-2-yn-1-yloxy)phenyl)methylene)bis(4-hydroxyquinolin-2(1H)-ones) with 4-azido-2-quinolones in good yields. This methodology allowed attaching three quinolone molecules via a triazole linker with the proposed mechanism. The products are interesting precursors for their anti-proliferative activity. Compound 8g was the most active one, achieving IC$_{50}$ = 1.2 ± 0.2 µM and 1.4 ± 0.2 µM against MCF-7 and Panc-1 cell lines, respectively. Moreover, cell cycle analysis of cells MCF-7 treated with 8g showed cell cycle arrest at the G2/M phase (supported by Caspase-3,8,9, Cytochrome C, BAX, and Bcl-2 studies). Additionally, significant pro-apoptotic activity is indicated by annexin V-FITC staining

Design, Synthesis, Molecular Docking, Antiapoptotic and Caspase-3 Inhibition of New 1,2,3-Triazole/Bis-2(1H)-Quinolinone Hybrids

A series of novel 1,2,3-triazoles hybridized with two quinolin-2-ones, was designed and synthesized through click reactions. The structures of the synthesized compounds were elucidated by NMR, IR, and mass spectra in addition to elemental analysis. The synthesized compounds were assessed for their antiapoptotic activity in testis, as testicular torsion is the main cause of male infertility. This effect was studied in light of decreasing tissue damage induced by I/R in the testis of rats using N-acetylcysteine (NAC) as an antiapoptotic reference. Compounds 6a–c were the most active antiapoptotic hybrids with significant measurements for malondialdehyde (MDA) and total antioxidant capacity (TAC) and the apoptotic biomarkers (testicular testosterone, TNFα, and caspase-3) in comparison to the reference. A preliminary mechanistic study was performed to improve the antiapoptotic activity through caspase-3 inhibition. A compound assigned as 6-methoxy-4-(4-(((2-oxo-1,2-dihydroquinolin-4-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)quinolin-2(1H)-one (6c) was selected as a representative of the most active hybrids in comparison to NAC. Assay of cytochrome C for 6c revealed an attenuation of cytochrome C level about 3.54 fold, comparable to NAC (4.13 fold). In caspases-3,8,9 assays, 6c was found to exhibit more potency and selectivity toward caspase-3 than other caspases. The testicular histopathological investigation was carried out on all targeted compounds 6a–g, indicating a significant improvement in the spermatogenesis process for compounds 6a–c if compared to the reference relative to the control. Finally, molecular docking studies were done at the caspase-3 active site to suggest possible binding modes. Hence, it could conceivably be hypothesized that compounds 6a–c could be considered good lead candidate compounds as antiapoptotic agents

Synthesis of novel 1,2-bis-quinolinyl-1,4-naphthoquinones : ERK2 inhibition, cytotoxicity and molecular docking studies

Two novel series of N-2,3-bis(6-substituted-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)naphthalene-1,4-diones 3a-d and substituted N-(methyl/ethyl)bisquinolinone triethyl-ammonium salts 4e,f were successfully synthesized. The synthesized compounds were targeted as new candidates to extracellular signal-regulated kinases 1/2 (ERK1/2) with considerable antineoplastic activity. The synthesis involved the reactions of 2 equivalents of 4-hydroxy-2(1H)-quinolinones la-f and one equivalent of 1,4-naphthoquinone (2) in a mixture of ethanol/dimethylformamide (1:1) as a solvent and 0.5 mL Et3N. In the reaction of 6-methyl-4-hydroxyquinolone 1b with 2, a side product 4b of the second series was obtained. In general, the presence of free NH-quinolone gave a single compound of the first series, whereas reaction of N-methyl/ethyl-quinolones 1e, f with 2 enhanced the formation of compounds of the second series. The structures of the new compounds were proved by different spectroscopic techniques such as IR, NMR (2D-NMR) and mass spectra, elemental analysis, and X-ray crystallography. To further elucidate the mechanism of action of these newly synthesized compounds, compounds 3a, 3b, 4e and 4f were selected to investigate for their MAP Kinases pathway inhibition together with molecular docking using ATP-binding site of ERK2. The results revealed that compounds 3a, 3b and 4f inhibited ETS-1 phosphorylation by ERK2 in a dose dependent manner. Also, compound 4f showed highest potency for ERK2 inhibition with ATPcompetitive inhibition mechanism which was confirmed by the formation of three hydrogen bond in the molecular docking studies. The synthesized compounds were then tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Interestingly, the selected compounds displayed from modest to strong cytotoxic activities. Compound 3b demonstrated broad spectrum anti-tumor activity against the nine tumor subpanels tested, while compound 3d proved to be lethal to most of the cancer cell lines as shown by their promising GI(50) and TGI values in NCI in vitro five dose testing. These results revealed that the synthesized compounds can potentially serve as leads for the development of novel chemotherapeutic agents and structure improvement will be necessary for some derivatives for enhancing their cellular activities and pharmacokinetic profile.Peer reviewe

Design, synthesis and biological evaluation of fused naphthofuro[3,2-c]quinoline-6,7,12-triones and pyrano[3,2-c]quinoline-6,7,8,13-tetraones derivatives as ERK inhibitors with efficacy in BRAF-mutant melanoma

Approximately 60% of human cancers exhibit enhanced activity of ERK1 and ERK2, reflecting their multiple roles in tumor initiation and progression. Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma and several other cancers. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Herein, we report the design and synthesis of novel series of fused naphthofuro[3,2-c] quinoline-6,7,12-triones 3a-f and pyrano[3,2-c]quinoline-6,7,8,13-tetraones 5a,b and 6, as potential ERK inhibitors. New inhibitors were synthesized and identified by different spectroscopic techniques and X-ray crystallography. They were evaluated for their ability to inhibit ERK1/2 in an in vitro radioactive kinase assay. 3b and 6 inhibited ERK1 with IC50s of 0.5 and 0.19 mu M, and inhibited ERK2 with IC50s of 0.6 and 0.16 mu M respectively. Kinetic mechanism studies revealed that the inhibitors are ATP-competitive inhibitors where 6 inhibited ERK2 with a K-i of 0.09 mu M. Six of the new inhibitors were tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Compound 3b and 6 were the most potent against most of the human tumor cell lines tested. Moreover, 3b and 6 inhibited the proliferation of the BRAF mutant A375 melanoma cells with IC50s of 3.7 and 0.13 mu M, respectively. In addition, they suppressed anchorage-dependent colony formation. Treatment of the A375 cell line with 3b and 6 inhibited the phosphorylation of ERK substrates p-90RSK and ELK-1 and induced apoptosis in a dose dependent manner. Finally, a molecular docking study showed the potential binding mode of 3b and 6 within the ATP catalytic binding site of ERK2.Peer reviewe

Diagnostic yield of combined magnetic resonance spectroscopy and diffusion weighted imaging in intracranial neoplasms

Purpose: Our intention was to evaluate the role of combined diffusion magnetic resonance imaging and spectroscopy in diagnosis and grading of brain tumors. Materials and methods: Ninety-three included cases underwent magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) of the brain lesion, stereotactic or open biopsies and histopathological examination. MRI protocol included DWI and calculated ADC values. Multivoxel MRS spectroscopic technique (MVS) was used and all MRS metabolic parameters were obtained. Results: High grade tumors had significantly lower ADC values than low grade tumors (P < 0.001). ADC values were the lowest in lymphoma (0.54 × 10−3 mm2/s) and the highest in craniopharyngioma (1.9 × 10−3 mm2/s). MRS revealed a statistically significant difference in CHO/NAA and CHO/Cr ratios between low and high grade tumors with P < 0.01 and P < 0.001, respectively. The mI/Cr ratio and presence of lactate, lipid and taurine also aided in differentiation and grading of brain tumors. The overall MRI/MRS sensitivity and specificity were 91%, 90.5%, respectively. Conclusion: MRS has a robust diagnostic accuracy in cases of well defined high or low grade brain neoplasms. ADC value had the ability to confirm and differentiate low from high grade tumors in many situations where there were diagnostic confusions with MRS due to borderline values