Benzoquinones

Purpose Pancreatic cancer (PC) is one of the deadliest of all tumors. Previously, we were the first to show that Thymoqui-none (TQ) derived from black seed (Nigella sativa) oil has anti-tumor activity against PC. However, the concentration of TQ required was ...

The spectroscopic characteristics of the solid charge-transfer molecular complexes (CT) formed in the reaction of the electron donor 4-(aminomethyl) piperidine (4AMP) with the σ-acceptor iodine and the π-acceptors 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCHD) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) have been studied in chloroform at 25°C. These were investigated through electronic, infrared spectra and thermal analysis as well as elemental analysis. The results show that the formed solid CT-complexes have the formulas [(4AMP)I](+)I3(-), [(4AMP)(DDQ)2] and [(4AMP)(TBCHD)] while in the case of 4AMP-TCNQ reaction, a short-lived CT complex is formed followed by rapid N-substitution by TCNQ forming the final reaction product 7,7,8-tricyano-8-aminomethylpiperidinylquinodimethane [TCAMPQDM] in full agreement with the known reaction stoichiometries in solution as well as the elemental measurements and the thermal analysis confirmed the structure of the obtained compounds. The formation constant kCT, molar extinction coefficient εCT, free energy change ΔG(0) and CT energy ECT have been calculated for the CT-complexes [(4AMP)I](+)I3(-), [(4AMP)(DDQ)2] and [(4AMP)(TBCHD)].

The high sequence conservation of druggable pockets of closely related proteins can make it challenging to develop selective inhibitors. We designed a new drug discovery approach that exploits both the static and dynamic differences of two orthologues. We applied it, as a proof of concept, to identify compounds that discriminate between the molecular chaperone Hsp90 of the protozoan pathogen Plasmodium falciparum (Pf) and that of its human host. We found that the ATP-binding pocket has a Pf-specific extension, whose sequence lining is identical in human Hsp90 but which differs by tertiary structure and dynamics. Using these insights for a structure-based drug screen, we discovered novel 7-azaindole compounds that exclusively bind the recombinant N-terminal domain of PfHsp90 but not of human Hsp90 nor of a PfHsp90 mutant with "human-like" dynamics. Moreover, these compounds preferentially inhibit the growth of yeast complemented by PfHsp90 and block the growth of Pf in culture.

Thymoquinone (TQ), the active constituent of Nigella sativa or black cumin exhibited cytotoxic effects in several cancer cell lines. In this study, the cytotoxicity of TQ in human cervical squamous carcinoma cells (SiHa) was investigated. TQ was cytotoxic towards SiHa cells with IC50 values of 10.67±0.12 and 9.33±0.19μg/mL as determined by MTT assay and trypan blue dye exclusion test, respectively,

NAPQI, i.e., N-acetyl-p-benzoquinone imine, is considered the toxic metabolite of the widely used analgesic drug paracetamol (acetaminophen, APAP). Due to its high reactivity towards nucleophiles both in low- and high-molecular-mass biomolecules, NAPQI is hardly detectable in its native form. Upon conjugation with glutathione, NAPQI is finally excreted in the urine as the paracetamol mercapturic acid. Thus, determination of paracetamol mercapturate may provide a measure of in vivo NAPQI formation. In this work, we propose the use of Na2S in aqueous solution to trap NAPQI and to analyze the reaction product, i.e., 3-thio-paracetamol, together with paracetamol by GC-MS/MS in the electron-capture negative-ion chemical ionization mode after solvent extraction with ethyl acetate and derivatization with pentafluorobenzyl bromide. In mechanistic studies, we used newly synthesized N-acetyl-p-[2,3,5,6-(2)H4]benzoquinone imine (d4-NAPQI). In quantitative analyses, N-(4-hydroxyphenyl)-[2,3,5,6...

Thymoquinone is the major active principle of Nigella sativa (N. sativa) and constitutes about 30% of its volatile oil or ether extract. N. sativa oil and seed are commonly used as a natural remedy for many ailments. Using modern scientific techniques, a number of pharmacological actions of N. sativa have been investigated including immunostimulant, anti-inflammatory, anticancer, antioxidant, antihistaminic, antiasthmatic, hypoglycemic, antimicrobial and antiparasitic. There are only few reports regarding the toxicity of thymoquinone. The present study was carried out to determine LD50 of thymoquinone both in mice and rats, orally as well as intraperitoneall, by the method of Miller and Tainter. Autopsy and histopathology of liver, kidney, heart and lungs were also determined. The LD50 in mice after intraperitoneal injection was determined to be 104.7 mg/kg (89.7-119.7, 95% confidence interval) and after oral ingestion was 870.9 mg/kg (647.1-1094.8, 95% confidence interval). Whereas...

A HPLC with gradient elution method for the determination of the synthetic phenolic antioxidants (SPAs) propyl gallate (PG), tertiary butyl hydroquinone (TBHQ), butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) in food items is described. A C18 column served as the stationary phase; the gradient elution was formed by acetonitrile and water:acetic acid (1%). The UV detector was set at 280 nm. Under the recommended conditions, separation of the four SPAs was achieved in less than 8 min. Analytical characteristics of the HPLC method such as limit of detection, linear range, and reproducibility were evaluated. Extraction parameters were optimized for the recoveries of the SPAs in different types of food items (cooking oil, margarine and butter, and cheese). Before the HPLC separation, the SPAs were extracted with methanol/acetonitrile (1:1, v/v) and were subjected to vortex/ultrasonic treatment. The extracts were next kept in a freezer (∼2 h) to precipitate co-extracted components. Recoveries of the SPAs when spiked to cooking oil, margarine, butter and cheese at 50 and 200 mg l−1 were in the ranges 93.3–108.3% for PG, 85.3–108.3% for TBHQ, 96.7–101.2% for BHA and 73.9–94.6% for BHT. The method was applied to the determination of SPAs in 38 food items (16 cooking oils, ten margarine, six butter and six cheese samples). The levels of SPAs in positive samples are all below the legal limits of Malaysia.

The effect of thymoquinone (TQ), the main constituent of the volatile oil of Nigella sativa seeds, on the nephropathy and oxidative stress induced by doxorubicin (DOX) in rats was investigated. A single intravenous injection of DOX (6 mg/kg) induced a severe nephrotic syndrome (after 5 weeks) associated with hypoalbuminemia, hypoproteinemia, elevated serum urea, hyperlipidemia, and a high urinary excretion of protein, albumin and N-acetyl-β-d-glucosaminidase (NAG). In the kidney, DOX induced a significant increase in total triglycerides (TG), total cholesterol (TC), and lipid peroxides and a significant decrease in non-protein sulfhydryl (NPSH) content and catalase (CAT) activity. Treatment of rats with TQ (10 mg/kg per day) supplemented with the drinking water for 5 days before DOX, and daily thereafter, significantly lowered serum urea, TG, and TC. Similarly, TG, TC and lipid peroxides in the kidneys of TQ-treated rats were decreased significantly compared with DOX alone. Moreover, NPSH content and CAT activity in the kidneys of TQ-treated DOX group were significantly elevated compared with DOX alone. Treatment with TQ significantly suppressed DOX-induced proteinuria, albuminuria, and urinary excretion of NAG. The results confirm the involvement of free radicals in the pathogenesis of nephropathy induced by DOX. Likewise, the study demonstrates the high antioxidant potential of TQ and its marked effect on the suppression of DOX-induced nephropathy. The data suggest that TQ might be applicable as a protective agent for proteinuria and hyperlipidemia associated with nephrotic syndrome.

A larger number of medicinal plants and their purified constituents have been shown beneficial therapeutic potentials. Seeds of Nigella sativa, a dicotyledon of the Ranunculaceae family, have been employed for thousands of years as a spice and food preservative. The oil and seed constituents, in particular thymoquinine (TQ), have shown potential medicinal properties in traditional medicine. In view of the recent literature, this article lists and discusses different immunomodulatory and immunotherapeutic potentials for the crude oil of N. sativa seeds and its active ingredients. The published findings provide clear evidence that both the oil and its active ingredients, in particular TQ, possess reproducible anti-oxidant effects through enhancing the oxidant scavenger system, which as a consequence lead to antitoxic effects induced by several insults. The oil and TQ have shown also potent anti-inflammatory effects on several inflammation-based models including experimental encephalomyelitis, colitis, peritonitis, oedama, and arthritis through suppression of the inflammatory mediators prostaglandins and leukotriens. The oil and certain active ingredients showed beneficial immunomodulatory properties, augmenting the T cell- and natural killer cell-mediated immune responses. Most importantly, both the oil and its active ingredients expressed anti-microbial and anti-tumor properties toward different microbes and cancers. Coupling these beneficial effects with its use in folk medicine, N. sativa seed is a promising source for active ingredients that would be with potential therapeutic modalities in different clinical settings. The efficacy of the active ingredients, however, should be measured by the nature of the disease. Given their potent immunomodulatory effects, further studies are urgently required to explore bystander effects of TQ on the professional antigen presenting cells, including macrophages and dendritic cells, as well as its modulatory effects upon Th1- and Th2-mediated inflammatory immune diseases. Ultimately, results emerging from such studies will substantially improve the immunotherapeutic application of TQ in clinical settings.

This in vitro study evaluated the antimicrobial activity of extracts obtained from Rheedia brasiliensis fruit (bacupari) and its bioactive compound against Streptococcus mutans. Hexane, ethyl-acetate and ethanolic extracts obtained (concentrations ranging from 6.25 to 800 μg/ml) were tested against S. mutans UA159 through MIC/MBC assays. S. mutans 5-days-old biofilms were treated with the active extracts (100×MIC) for 0, 1, 2, 3 and 4 h (time-kill) and plated for colony counting (CFU/ml). Active extracts were submitted to exploratory chemical analyses so as to isolate and identify the bioactive compound using spectroscopic methods. The bioactive compound (concentrations ranging from 0.625 to 80 μg/ml) was then tested through MIC/MBC assays. Peel and seed hexane extracts showed antimicrobial activity against planktonic cells at low concentrations and were thus selected for the time kill test. These hexane extracts reduced S. mutans biofilm viability after 4 h, certifying of the bioactive compound presence. The bioactive compound identified was the polyprenylated benzophenone 7-epiclusianone, which showed a good antimicrobial activity at low concentrations (MIC: 1.25–2.5 μg/ml; MBC: 10–20 μg/ml). The results indicated that 7-epiclusianone may be used as a new agent to control S. mutans biofilms; however, more studies are needed to further elucidate the mechanisms of action and the anticariogenic potential of such compound found in R. brasiliensis.

We show that HTLV-1 negative leukemia cells are more sensitive to TQ due to higher levels of drug-induced reactive oxygen species (ROS). PreG1 population in HTLV-1 negative Jurkat and CEM was higher than HTLV-1 transformed HuT-102 and MT-2 cells. Peripheral blood mononuclear cells were more resistant. Hoechst staining indicated more features of apoptosis, namely nuclear blebs and shrunken nuclei in HuT-102 than Jurkat. A greater depletion of the antioxidant enzyme glutathione occurred in Jurkat, which consequently led to an increase in ROS, loss of mitochondrial membrane potential, cytochrome c release, activation of caspases 3 and 9, and cleavage of PARP. Treatment with z-VAD-fmk partially reversed TQ-induced apoptosis, suggesting a caspase-dependent mechanism. N-acetyl cysteine prevented apoptosis providing evidence that cell death is ROS-dependent. Catalase prevented apoptosis to a lesser extent than NAC. In summary, TQ induces apoptosis in adult T cell leukemia/lymphoma by decre...