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In the early stages of drug discovery, adequate evaluation of the potential drug–drug interactions (DDIs) of drug candidates is important. Several CYP3A activators are known to lead to underestimation of DDIs. These compounds affect midazolam 1'-hydroxylation but not midazolam 4-hydroxylation. We used both metabolic reactions of midazolam to evaluate the activation and inhibition of CYP3A activators simultaneously. For our CYP inhibition assay using cocktail probe substrates, simultaneous liquid chromatography-tandem mass spectrometry monitoring of 1'-hydroxymidazolam and 4-hydroxymidazolam for CYP3A was established in addition to monitoring of 4-hydroxydiclofenac and 1'-hydroxybufuralol for CYP2C9 and CYP2D6. The results of our cocktail inhibition assay were well correlated with those of a single inhibition assay, as were the estimated inhibition parameters for typical CYP3A inhibitors. In our assay, a proprietary compound that activated midazolam 1'-hydroxylation and tended to inhibit 4-hydroxylation was evaluated along with known CYP3A activators. All compounds were well characterised by comparison of the results of midazolam 1'- and 4-hydroxylation. In conclusion, our CYP cocktail inhibition assay can detect CYP3A activation and assess the direct and time-dependent inhibition potentials for CYP3A, CYP2C9, and CYP2D6. This method is expected to be very efficient in the early stages of drug discovery. [ABSTRACT FROM AUTHOR]

Thermal treatment of coal byproducts has been shown to improve leaching characteristics of rare earth elements (REEs) in bituminous coal sources due to its influence on the associated minerals. This study investigated the impact of the calcination atmosphere on REE leaching behavior in different density fractions of Baker and Fire Clay seam coarse refuse sources using a thermogravimetric analyzer to create an oxidizing or reducing atmosphere at a desired temperature for 2 h. The effect on leaching characteristics was evaluated using 1.2 M sulfuric acid at 75°C for 5 h at 1% w/v solid concentration. Rare earth element (REE) recovery for the 2.2 specific gravity (SG) sink fraction improved by approximately 15 absolute percentage points at 1000°C relative to the 600°C calcined sample in an inert atmosphere and equilibrated within 10 min from the start of the test. Contrarily, thermal treatment at 1000°C under oxidizing atmosphere significantly reduced the REE recovery due to sintering of the clays, which limited access to the RE minerals for leaching. In general, thermal treatment of heavier fractions in both atmospheres significantly improved the light REE (LREE) recovery while the increase in heavy REE (HREE) recovery was relatively less. As common clay minerals in the coal sources, kaolinite and illite samples were tested under the same conditions and using a digital scanning calorimeter. The findings confirmed that the improvement observed in REE leaching through thermal treatment at 600°C was due to decarbonization for the lighter density fractions and dehydroxylation of clays. [ABSTRACT FROM AUTHOR]

Acid baking treatment is widely used to extract rare earth elements (REEs) from refractory rare earth bearing minerals such as monazite and xenotime. Since these REE minerals have been identified in coal-based sources, a parametric study was conducted to evaluate the impact and optimize the parametric values associated with the acid-baking process when treating a bituminous coal source. The parameters studied using a three-level statistical experimental program were acid baking time, acid solution concentration, baking temperature, and acid solution-to-solids ratio and each were found to significantly impact REE and contaminant element recovery. An increase in baking temperature up to around 250°C improved the light and heavy REE recovery values by more than 50 absolute percentage points relative to performances achieved when direct leaching. Acid baking was needed to dehydroxylate the clays and liberate the REE minerals, which allowed access for the acid to solubilize the REEs. Acid concentration of the solution used for acid baking was studied as a means of minimizing the amount of acid needed to achieve a target REE recovery. However, thermo-gravimetric and differential scanning calorimetry analysis (TGA-DSC) of sulfuric acid under oxidizing atmosphere revealed that the addition of water decreased the evaporation temperature, which explains the lower REE recovery values obtained when using lower acid concentrations. Using pure sulfuric acid at an acid-to-solid ratio of 0.8:1 resulted in recovery values of around 70% for both LREEs and HREEs. The decomposition reaction time was relatively quick with 65% of the TREEs recovered within the first 10 minutes. Water leaching experiments performed on the acid-baked products under a temperature of 25°C instead of 75°C revealed an increase in REE recovery by 10 absolute percentage points, which was likely due to the high solubility of REE-sulfates at room temperatures. [ABSTRACT FROM AUTHOR]

Abstract This work highlighted the proficient and naturally safe methodology for the phenol synthesis using biocatalyst lipase. The development of sustainable synthetic protocol for various organic transformations is an important area of research attracts researchers to avoid use of volatile and hazardous organic solvents in reaction for greener and eco-friendly protocols. Lipase is subclass of esterase enzymes and acts as biocatalyst with industrial significance. They carry out biochemical transformation in non-aqueous and aqueous phases quickly. To further make the process more specific Design Expert software was used for the optimization of synthesize phenol for maximum % Yield and % Purity. Effect of temperature, Concentration of Catalyst, and Volume of Water was selected as an independent factor to get the maximum % Yield and % Purity of the phenol. The results confirmed the mathematical model robustness and justify experimental design. Therefore, the current protocol for synthesis of phenols from phenylboronic acid is greenest and environmentally benign alternative. The current convention has many benefits, like phenomenal product yields, reduced time of reaction, simple procedure to work up, and extensive substrate scope, cost-effective and also lipase was recuperated and reused multiple times without significant loss of its catalytic activity. [ABSTRACT FROM AUTHOR]

A highly efficient protocol was developed for the ipso hydroxylation of arylboronic acids using citric acid as an effective organocatalyst. The sustainable methodology offers good to excellent yields with in the rapid reaction time in water as a solvent media and 30% H2O2 as an oxidant. The reaction proceeds without the aid of any metal catalyst or base and is simple, safe, and clean. The current protocol enables the access to variety of phenols and is found to be tolerable to the diverse electronic substrates. Even, the devised reaction conditions have been found to be effective in the gram-scale synthesis of an API, Mequinol. [ABSTRACT FROM AUTHOR]

The induction assay for the cytochromes P450 (P450s) is an important tool in drug discovery and development. The inductions of dog P450 1A2 and 3A12 by omeprazole and rifampicin were functionally characterised in dog hepatocytes and were compared with induction in human HepaRG and HepaSH cells. P450 1A2-dependent ethoxyresorufin O-deethylation was induced by R,S-omeprazole and P450 3 A-dependent midazolam 1′-hydroxylation was induced by rifampicin, and both reactions were significantly enhanced in cultured dog hepatocytes and human HepaRG and HepaSH cells. Recombinant dog P450 1A2 exhibited activities towards R- and S-omeprazole 5-hydroxylation with low Km values of 23–28 µM, whereas dog P450 2C21 and 3A12 efficiently mediated S-omeprazole 5-hydroxylation and sulfoxidation, respectively, with high Vmax values of 12–17 min−1. Although omeprazole 5-hydroxylation by human P450 2C19 (and sulfoxidation by P450 3A4) in human HepaSH cells were slightly (∼2-fold) induced by R,S-omeprazole, dog P450 1A2 was autoinduced by omeprazole in dog hepatocytes and showed enhanced R-omeprazole 5-hydroxylation activity (∼5-fold). These results indicate that omeprazole can be an autoinducer of P450 1A2 in hepatocytes, and this enzyme was found to be involved in omeprazole 5-hydroxylation and sulfoxidation in dog hepatocytes and human HepaRG and HepaSH cells. [ABSTRACT FROM AUTHOR]

The 2-oxidation, 3-methyl hydroxylation, and 6-hydroxylation of skatole (a contributor to boar taint) mediated by minipig liver microsomes and recombinant P450 enzymes expressed in bacterial membranes were investigated. At low substrate concentrations of 10 µM, the formation rates of indole-3-carbinol, 6-hydroxyskatole, and the sum of 3-methyloxindole, indole-3-carbinol, and 6-hydroxyskatole in male minipig liver microsomes were significantly lower than those in female minipig liver microsomes. Compensatory 3-methyloxindole and indole-3-carbinol formation in minipig liver microsomes, which lack 6-hydroxyskatole formation in males, was mediated partly by liver microsomal P450 1A2 and P450 1A2/2E1, respectively. These enzymes were suppressed by typical P450 inhibitors in female minipig liver microsomes. Among the 14 pig P450 forms evaluated, P450 2A19 was the dominant form mediating 3-methyloxindole, indole-3-carbinol, and 6-hydroxyskatole formation from skatole at substrate concentrations of 100 µM. Positive cooperativity was observed in 3-methyloxindole formation from skatole mediated by male minipig liver microsomes and by pig P450 3A22 with Hill coefficients of 1.2–1.5. These results suggest high skatole 2-oxidation, 3-methyl hydroxylation, and 6-hydroxylation activities of pig P450 2A19 and compensatory skatole oxidations mediated by pig P450 1A2, 2E1, or 3A22 in male minipig liver microsomes. [ABSTRACT FROM AUTHOR]

Flavonoids are widely distributed in plants and constitute the most common polyphenolic phytoconstituents in the human diet. In this study, the in vitro inhibitory activity of 44 different flavonoids (1-44) against mushroom tyrosinase was studied, and an in silico study and type of inhibition for the most active compounds were evaluated too. Tyrosinase inhibitors block melanogenesis and take part in melanin production or distribution leading to pigmentation diseases. The in vitro study showed that quercetin was a competitive inhibitor (IC50=44.38±0.13 µM) and achieved higher antityrosinase activity than the control inhibitor kojic acid. The in silico results highlight the importance of the flavonoid core with a hydroxyl at C7 as a strong contributor of interference with tyrosinase activity. According to the developed statistical model, the activity of molecules depends on hydroxylation at C3 and methylation at C8, C7, and C3 in the benzo-γ-pyrane ring of the flavonoids. [ABSTRACT FROM AUTHOR]

An enantioselective total synthesis of novel gingerol-related compound 4-((3S,5R)-3,5-dihydroxynonadecyl)phenol, an anti-oxidant isolated from the resinous exudates of Chilean desert plants, has been accomplished from a known commercially available 4-(but-3-enyl) phenol by a concise ten-step sequence. In this synthesis, Sharpless asymmetric dihydroxylation, Grignard reaction and Iodine-induced electrophilic cyclization have been applied as key steps. [ABSTRACT FROM AUTHOR]

A new and simple method for synthesizing iodohydrins and iodoethers from aromatic alkenes is described. Iodohydrins and iodoether derivatives were prepared in excellent yield using Mercury(II) tetrafluoroborate (Hg(BF4)2.SiO2)/I2 in aqueous THF or alcohols (methanol, iso-propanol and tert-butanol). The reactions take place at room temperature, short reaction times, and high regioselectivity, following Markovnikov fashion. [ABSTRACT FROM AUTHOR]

Titanium dioxide (TiO2) is one of prototype, water-splitting catalysts, while its catalytic performance is strongly affected by the presence of water molecules or hydroxyl groups on the surface. The adsorption of water on the TiO2(101) and TiO2(001) surfaces at different water/hydroxyl coverages was firstly studied using density functional theory (DFT) calculations. It has been found that the surface hydroxylation state has a significant influence on water adsorption behaviour. On the basis of calculated Gibbs free surface energies as a function of temperature and hydroxylation extent, the fully dehydrated TiO2(101) and TiO2(001) surfaces will be reached at 500 and 1000 K, respectively. In the present work, BF3 and NH3 were used as probe molecules to study the Lewis acidic and Brønsted basic strengths of TiO2(101) and TiO2(001) surfaces under different hydroxylation conditions. As the hydroxyl coverage increases, the Brønsted basic strength becomes stronger while the Lewis acidic strength is weakened. Finally, it is noted that the TiO2 surface is slightly oxidised at low hydroxyl coverage but being reduced at high hydroxyl coverage. [ABSTRACT FROM AUTHOR]

Phenols are prominent in organic reactions and highly significant biologically active substances. We report a versatile and sustainable CuI-catalyzed protocol for their synthesis through an oxidative ipso-functionalization (hydroxy deborylation) strategy of (hetero)arylboronic acids [(H)ABAs] using the water extract of pomegranate peel ash (WEPA) in open-air. They are formed at room temperature (RT). This process shows high significance toward the environmental sustainability over the reported procedures of ipso-hydroxylation of (H)ABAs. The application of a waste-derived biorenewable basic reaction medium, air as an oxidant, wide substrate scope, high functional group tolerance, reusability of the catalyst, ambient conditions, less expensive and safer catalyst with low loading, aqueous medium, avoidance of volatile organic solvents, and external oxidant, and tremendous further scope are the noteworthy features of this protocol. [ABSTRACT FROM AUTHOR]

We report a stereoselective total synthesis of a natural product, phomonol, from readily available D-aspartic acid. The key steps include Wittig olefination, Sharpless asymmetric dihydroxylation, Grignard addition, diastereoselective reductive etherification and Wacker oxidation. [ABSTRACT FROM AUTHOR]

Pirfenidone is a first-line drug for the treatment of idiopathic pulmonary fibrosis. The primary metabolic pathways of pirfenidone in humans are 5-hydroxylation and subsequent oxidation to 5-carboxylpirfenidone. The aims of this study were to determine the cytochrome P450 isoforms responsible for pirfenidone 5-hydroxylation and to evaluate their contributions in human liver microsomes (HLM). Among the recombinant P450 isoforms, CYP1A2, CYP2D6, CYP2C19, CYP2A6, and CYP2B6 were shown to catalyse the 5-hydroxylation of pirfenidone. Pirfenidone 5-hydroxylase activity by HLM was inhibited by α-naphthoflavone (by 45%), 8-methoxypsolaren (by 84%), tranylcypromine (by 53%), and quinidine (by 15%), which are CYP1A2, CYP1A2/CYP2A6/CYP2C19, CYP2A6/CYP2C19, and CYP2D6 inhibitors, respectively. In 17 individual HLM donors, pirfenidone 5-hydroxylase activity was significantly correlated with phenacetin O-deethylase (r = 0.89, P < 0.001) and S-mephenytoin 4'-hydroxylase activities (r = 0.51, P < 0.05), which are CYP1A2 and CYP2C19 marker activities, respectively. By using the relative activity factors, the contributions of CYP1A2, CYP2C19, and CYP2D6 to pirfenidone 5-hydroxylation in the human liver were 72.8%, 11.8%, and 8.9%, respectively. In conclusion, we clearly demonstrated the predominant P450 involved in pirfenidone 5-hydroxylation in the human liver is CYP1A2, with CYP2C19 and CYP2D6 playing a minor role. [ABSTRACT FROM AUTHOR]

Hydroxytyrosol (4-(2-hydroxyethyl)-1,2-benzenediol) is the most known bioactive compound from the plant Olea europaea (olive tree). To date, few biocatalysis processes allowing efficient production of hydroxytyrosol from potential substrates including, tyrosol (2-(4-hydroxy) phenyl ethanol) and tyrosine have been reported. In this paper, we report for a Gram-positive bacterium that produces hydroxytyrosol via conversion of tyrosol and/or L-tyrosine, identified as a Rhodococcus pyridinivorans based on phenotypic characteristics and 16S rDNA sequence, and designated R. pyridinivorans strain 3HYL DSM109178. Interestingly, strain 3HYL shows an outstanding production of hydroxytyrosol from tyrosol up to 16.4 ± 0.23 mmol/L with high kinetic parameters exceeding the reported values. However, a slight downstream metabolism of the product is assigned to the wild-type strain during the stationary phase of growth. The plasmid-cured strain was obtained using random chemical mutagenesis, designated R. pyridinivorans 3HYL-AO, and was able to produce hydroxytyrosol, with yields up to 21.75 ± 0.34 mmol/L. Moreover, the plasmid-cured strain exhibited a significant reduction in the transformation to its acetic acid forms compared to the wild-type strain as depicted by HPLC analysis. Comparison of kinetic data of the bioconversion/accumulation process between the wild type and mutant strain, in the presence and absence of L-tyrosine, and thus suggesting the occurrence of an upstream pathway for synthesis of tyrosol via (L)-tyrosine. [ABSTRACT FROM AUTHOR]

In this work, biotransformations of dehydroepiandrosterone (DHEA) 1 by Ulocladium chartarum MRC 72584, Cladosporium sphaerospermum MRC 70266 and Cladosporium cladosporioides MRC 70282 have been reported. U. chartarum MRC 72584 mainly hydroxylated 1 at C-7α and C-7β, accompanied by a minor hydroxylation at C-4β, a minor epoxidation from the β-face and a minor oxidation at C-7 subsequent to its hydroxylations. 3β,7β-Dihydroxy-5β,6β-epoxyandrostan-17-one 6, 3β,4β,7α-trihydroxyandrost-5-en-17-one 7 and 3β,4β,7β-trihydroxyandrost-5-en-17-one 8 from this incubation were identified as new metabolites. C. sphaerospermum MRC 70266 converted some of 1 into a 3-keto-4-ene steroid and then hydroxylated at C-6α, C-6β and C-7α, accompanied a minor 5α-reduction and a minor oxidation at C-6 following its hydroxylations. C. sphaerospermum MRC 70266 also hydroxylated some of 1 at C-7α and C-7β. C. cladosporioides MRC 70282 converted almost half of 1 into a 3-keto-4-ene steroid and then hydroxylated at C-6α and C-6β. C. cladosporioides MRC 70282 also reduced some of 1 at C-17. [ABSTRACT FROM AUTHOR]

The thermal-decomposition behavior of a sodium-bentonite sample was investigated in this study. Non-isothermal pyrolysis tests were performed through simultaneous thermogravimetric (TG) and differential scanning calorimetry (DSC) analysis to characterize the thermal-behavior of the bentonite sample in a temperature range from ambient to 750°C. X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and Scanning electron microscopy (SEM) were used to determine the changes in mineralogy, structural features and morphology of bentonite before and after pyrolysis at 750°C. Iso-conversional methods were used to obtain kinetic-parameters such as the activation energies whereas Coats-Redfern (CR) method was used to find the most probable reaction mechanisms involved on the bentonite pyrolysis. XRD analysis showed that bentonite sample was mainly composed of sodium montmorillonite and a minority of other minerals such as quartz, plagioclase, alkali feldspar, cristobalite and calcite. Structural collapse of the clay mineral due to the thermal treatment was confirmed through XRD, FT-IR and SEM. Results indicated that thermal-decomposition of bentonite is carried out in two stages: a dehydration following a diffusion-controlled kinetics with an average activation energy of 72.23 kJ/mol, and a dehydroxylation characterized by a second-order kinetics with an average activation energy of 228.28 kJ/mol. [ABSTRACT FROM AUTHOR]

Nine forms of recombinant cytochrome P450 (P450 or CYP) enzymes were used to study roles of individual P450 enzymes in the oxidation of flavone and some other flavonoids, 4′-hydroxyflavone and 4′-, 3′-, and 2′-methoxyflavones, by human liver microsomes using LC-MS/MS analysis. As has been reported previously , 4′-, 3′-, and 2′-methoxyflavones were preferentially O-demethylated by human liver P450 enzymes to form 4′-, 3′-, and 2′-hydroxylated flavones and also 3′,4′-dihydroxyflavone from the former two substrates. In comparisons of product formation by oxidation of these methoxylated flavones, CYP2A6 was found to be a major enzyme catalysing flavone 4′- and 3′-hydroxylations by human liver microsomes but did not play significant roles in 2′-hydroxylation of flavone, O-demethylations of three methoxylated flavones, and the oxidation of 4′-hydroxyflavone to 3′,4′-dihydroxyflavone. The effects of anti-CYP2A6 IgG and chemical P450 inhibitors suggested that different P450 enzymes, as well as CYP2A6, catalysed oxidation of these flavonoids at different positions by liver microsomes. These studies suggest that CYP2A6 catalyses flavone 4′- and 3′-hydroxylations in human liver microsomes and that other P450 enzymes have different roles in oxidizing these flavonoids. [ABSTRACT FROM AUTHOR]

Two new milbemycin metabolites, 13α-hydroxymilbemycin β13 (1) and 26-methyl-13α-hydroxymilbemycin β13 (2), were isolated from the fermentation broth of a genetically engineered strain Streptomyces avermitilis AVE-H39. Their structures were determined by the comprehensive spectroscopic data, including 1 D, 2 D NMR, MS spectral analysis and the comparison with data from the literature. Compounds 1 and 2 not only exhibited potent acaricidal activities against Tetranychus cinnabarinus, but also had nematocidal activity against Bursaphelenchus xylophilus. [ABSTRACT FROM AUTHOR]

Symmetric and asymmetric dihydroxylation reactions catalyzed by osmium have emerged as the most efficient route in the one-step synthesis of diols. This is because on an industrial scale 1,2-diols are prepared via a two-step procedure. Still, it is a challenge to prepare and apply osmium catalysts in dihydroxylation catalysis because of their safety and environmental implications; e.g., volatile, highly toxic, product contamination, etc. To date, few efforts were reported to comprehensively overcome these drawbacks with great success by heterogenizing to an insoluble matrix, including diminishment in catalytic performance. Hence, the need for efficacious solid-supported osmium catalysts to subdue these difficulties is a topic of great importance. This mini review provides a concise overview of some of the most encouraging solid-supported osmium catalysts reported over the last few years, which proved to be more efficient under mild conditions as opposed to other immobilized osmium catalytic systems. The summary discusses the latest developments in the synthetic heterogenizing and homogenization strategies, structure analysis and investigation toward symmetric and asymmetric dihydroxylation for diol production. Specific emphasis is focused on their mechanistic considerations, their reusability and improvement in their safety, and environmental implications. [ABSTRACT FROM AUTHOR]