Oxidation Of Phenothiazines Research Articles

Oxidation of phenothiazines by human term placental peroxidase in non‐smokers

Oxidation of phenothiazines by human term placental peroxidase in non‐smokers

Oxidation of phenothiazines by human term placental peroxidase in non-smokers

Several phenothiazine derivatives have been shown to cause reproductive toxicity. The biochemical mechanisms responsible for these effects are not fully understood at present. In this study, we investigated hydrogen peroxide-dependent oxidation of seven phenothiazines by purified human term placental peroxidase. Promazine was employed as the prototype phenothiazine drug. Promazine was easily oxidized to a cation radical (absorption maximum at 513 nm) when incubated under acidic conditions with human term placental peroxidase in the presence of hydrogen peroxide. The rate of the radical formation was 350 +/- 30 nmol/min/mg protein when 30 micrograms of the purified peroxidase was incubated with 10 mM promazine and 1.0 mM hydrogen peroxide in acetate buffer pH 3.5. The reaction was linear with respect to time, exhibited dependence on the amount of enzyme, and the concentration of promazine and hydrogen peroxide. Collectively, the results suggest an enzymatic nature of the reaction. Reduced glutathione, ascorbate, and NADH suppressed the rate of promazine radical formation presumably by its reduction back to promazine in a concentration-dependent manner. Concomitantly, NADH was co-oxidized. The cation radical formation and NADH oxidation declined significantly by potassium cyanide and sodium azide, the known peroxidase inhibitors. The enzyme also oxidized chlorpromazine, triflupromazine, trifluoperazine, trimeprazine, fluphenazine, and perphenazine in the presence of hydrogen peroxide. The evidence gathered in this study suggests that peroxidative bioactivation of phenothiazines to their corresponding cation radical species by the human placental peroxidase may represent one of the biochemical mechanisms responsible for the reported developmental toxicity of these chemicals.

Enzymatic oxidation of phenothiazines by lipoxygenase/H 2O 2 system

Lipoxygenase (LOX) (EC 1.13.11.12) oxidized a wide range of phenothiazine (Pt) tranquillizers to their corresponding radical cations in the presence of H 2O 2 by means of an enzymatic chemical second-order mechanism with substrate regeneration similar to that of horseradish peroxidase. The optimum pH of LOX for this hydroperoxidase activity was in the acid range (pH 3.0–4.0), as has been shown for other Pt oxidizing systems, such as peroxidase/H 2O 2 and haemoglobin. LOX showed Michaelis constants for Pt ranging from 1.4 to 8.5 mM and which, in some cases, e.g. trifluoperazine, displayed substrate inhibition. By contrast, it had a high affinity for H 2O 2 in the μM to mM range. A new, previously undescribed plot, which relates the enzymatic affinity and the apparent second-order decay of the cation radical, was developed to study the influence of the 2- and 10-substituents in the Pt ring. The implications of this new plot and the LOX-mediated Pt oxidation are also discussed.

Chemical and electrochemical oxidation of phenothiazine

The oxidation of phenothiazine in dilute solutions of sulphuric acid leads to the corresponding cation radical. Using a potentiometric technique, a pKa value of 5.72 ± 0.05 was determined for phenothiazine. The kinetics has been studied and participation of both protonated and unprotonated oxidant in the oxidation reaction has been confirmed. Using a voltammetric technique with a rotating disk electrode, the anodic oxidation of phenothiazine was shown to be a one-electron diffusion-controlled process. A quantum chemical explanation was found for the direction of phenothiazine protonation and the absence of a dimerization stage of oxidation.

A kinetic study of the generation and decomposition of some phenothiazine free radicals formed during enzymatic oxidation of phenothiazines by peroxidase-hydrogen peroxide

A kinetic study of the oxidation of four different phenothiazines (Pts) by peroxidase-hydrogen peroxide was carried out. The free radical formed during the enzymatic oxidation suffers a non-enzymatic breakdown and the overall system was analysed and characterized. The non-enzymatic breakdown of the cation radical does not occur through a disproportionation mechanism but through a more complex mechanism. The kinetic parameters of the overall system were determined for the different Pts. These experimental data may serve in the understanding of the pharmacological action of Pts.

Determination of the molar absorptivities of phenothiazine cation radicals generated by oxidation with hydrogen peroxide/peroxidase

Phenothiazines are used an antipsychotic drugs and as reagents to determine microamounts of hemoglobin in biological fluids and tissues. Several agents cause the oxidation of phenothiazines to chromophoric cation radicals, whose stability may be related with their biological action. Enzymes and proteins with peroxidase activity catalyze the oxidation by H 2O 2 of phenothiazines to their corresponding cation radicals, which suffer a non-enzymatic breakdown. The instability of these cation radicals makes the determination of their respective molar absorptivities very difficult. These properties, however, have been determined for a few phenothiazine cation radicals by cumbersome or unreliable procedures. In this paper a new method is proposed and applied to six different phenothiazines oxidized with H 2O 2/peroxidase. The method involves the stoichiometric exhaustion of H 2O 2, under assay conditions which yield a fast enzymatic formation of phenothiazine cation radicals and which slow down their nonezymatic breakdown. This method may be useful for quantitative studies on the enzymatic activity and the reaction mechanism of the oxidation of a number of phenothiazines catalyzed by different types of peroxidase, as well as by proteins with peroxidase activity, such as hemoglobin.

Kinetics and mechanism of oxidation of N-substituted phenothiazines by chromium(VI)

The kinetics of oxidation of N-acetylphenothiazine (NAPT) by Cr(VI) in 80% acetic acid-20% water (v/v) mixture is first-order each in [NAPT] and [Cr(VI)]. The reaction is catalysed by added acid with a third-order dependence in [HCIO4], Increase in polarity of the solvent medium decreases the rate. The oxidation is insensitive to variations in ionic strength as well as added acrylamide. Oxidations of phenothiazine (PT) and N-methylphenothiazine (NMPT) under similar conditions are found to be very fast. However kinetic investigations with NMPT in an acetic acid-sodium acetate buffer show first-order dependence each in [NMPT] and [Cr(VI)] and a fractional-order dependence in [H+] in the pH range 1.80-3.09. Increase in polarity of the medium increases the rate. In both the cases, the corresponding sulphoxides are identified as oxidation products. Based on the kinetic results, mechanisms for oxidations are proposed.

Resonance Raman Spectra of Intermediates in Oxidation of Phenothiazine and Phenoxazine

Resonance Raman Spectra of Intermediates in Oxidation of Phenothiazine and Phenoxazine

Flow injection method for the assay of phenothiazine neuroleptics in pharmaceutical preparations using ammonium metavanadate

A simple flow injection method for the determination of chlorpromazine, promethazine, trimeprazine and perphenazine over wide ranges of concentrations is described. The method is based on the oxidation of phenothiazine with ammonium metavanadate in sulphuric acid media and subsequent measurement of the coloured, oxidized form of the product at the corresponding wavelength. A sampling rate of up to 160 h–1 was attained. Relative standard deviations for the standard samples were usually less than 0.5%. The method was applied to the determination of phenothiazines in proprietary drugs and the results were comparable to those obtained by the official methods in the British Pharmacopoeia.

ChemInform Abstract: Convenient Oxidation of Phenothiazine Salts to Their Sulfoxides with Aqueous Nitrous Acid.

A Simple method is reported for the preparation of gram quantities of phenothiazine sulfoxides by aqueous nitrous acid oxidation of phenothiazines at room temperature. The chiral levomepromazine gave rise to diastereoisomeric products analogous to those reported for thioridazine sulfoxidation.

Convenient oxidation of phenothiazine salts to their sulfoxides with aqueous nitrous acid.

A simple method is reported for the preparation of gram quantities of phenothiazine sulfoxides by aqueous nitrous acid oxidation of phenothiazines at room temperature. The chiral levomepromazine gave rise to diastereoisomeric products analogous to those reported for thioridazine sulfoxidation.

Solvent effect on the kinetics of the electrooxidation of phenothiazine

One-electron oxidation of phenothiazine to the corresponding radical cation was used as a model system to study the solvent effect on the heterogeneous charge-transfer kinetics. The standard rate constant of the studied electrode reaction was found to depend considerably on the nature of the solvent. The experimental kinetic data has been interpreted in terms of the dielectric dynamic properties of the solvent. The linear relationships between the standard rate constant and the reciprocal of the longitudinal dielectric relaxation time of a given solvent have been found in the aprotic case as well as for hydrogen-bonded solvents. The difference between both groups of solvents may be explained by the different dielectric relaxation behaviour or by the difference in the reaction site in respect to the electrode surface.

Free radical induced one-electron oxidation of the phenothiazines chlorpromazine and promethazine

Absolute rate constants have been measured for the reactions of the protonated forms of chlorpromazine and promethazine, CZH+ and PZH+, with the electrophilic radicals ˙OH, Br2–˙, (SCN)2–˙, I2–˙, N3˙, TI2+, TI(OH)+, (t-C4H9S t-C4H9)+˙, (CH3SSCH3)+˙, and lipoate+˙ in the pH range 2–8. Values for these one-electron oxidations vary from k= 3.1 × 108 mol–1 dm3 s–1 for [(t-C4H9S t-C4H9)+˙+ PZH+] to 5.5 × 109 mol–1 dm3 s–1 for (Br2–˙+ CZH+). The yields of the oxidation products, PTZH2+˙, vary from 28% for (˙OH + CZH+) to 97% for [(SCN)2˙–+ CZH+]. The PTZH2+˙ radical cations exhibit characteristic absorption spectra with two maxima around 270 and 510 nm, and extinction coefficients of Iµ(CZH2+˙)= 56 000 mol–1 dm3 cm–1 at 270 nm and 12 000 mol–1 dm3 cm–1 at 510 nm, and Iµ(PZH2+˙)= 62 500 mol–1 dm3 cm–1 at 265 nm and 9 500 mol–1 dm3 cm–1 at 505 nm. A transient absorption around 350 nm observed in the reaction of the phenothiazines with hydroxyl radicals is most probably the ˙OH–adduct, PTZH(OH)+˙. The mechanism of the ˙OH-radical-induced oxidation of phenothiazines suggested in an earlier publication has been confirmed and enlarged.

Study of the electrochemical oxidation of phenothiazine derivatives in acetonitrile medium: The effect of the structure on the voltammetric behavior

The electrochemical oxidation of phenothiazine and its derivatives substituted in the 2 and 10 positions was studied. The voltammetric behavior of the studied substances was compared. An attempt was made to quantitatively characterize the effect of the substituents. The reversibility of electrode reaction was studied by CV method. Values of diffusion coefficients of phenothiazine derivatives in anhydrous acetonitrile medium were estimated; these values have not yet been published.

Kinetic and spectroscopic studies with a rapid-scanning spectrometer. Part 2. Intermediates in the one-equivalent metal ion oxidation of phenothiazine and phenoxazine

The one-equivalent oxidations of phenothiazine and phenoxazine (Ar2NH) in neutral and acidic CH3CN solution by CeIV and FeIII have been analysed kinetically into the sequence Ar2NH [graphic omitted] Ar2NH˙+ [graphic omitted] Ar2N+→ product and values (or limits) for the relevant rate constants, including those for the oxidant–cation radical reaction, obtained by stopped-flow or rapid-scanning spectrometry. The latter technique has provided u.v.–visible spectra of all the intermediates involved, of which some are described for the first time.

Benzophenone-sensitized oxidation of phenothiazine

Oxidation of phenothiazine sensitized by benzophenone gives 3-phenothiazone and phenothiazine-5-oxide as the primary products at low conversions in benzene. From the kinetic features a mechanism demonstrating energy transfer from triplet benzophenone to phenothiazine has been postulated. Triplet phenothiazine is shown to undergo oxidation essentially without any participation of O 2 ( 1Σ g + or 1Δ g). No charge transfer complexation between the sensitizer and substrate is observed. The presence of hydroxylic solvents increases the net reaction and this effect has been discussed.

Heterocyclic free radicals. Part 9. The single-electron oxidation of phenothiazine and its methylated derivatives by diazonium ions

In acidified acetonitrile the reaction of certain phenothiazines with diazonium ions leads to the formation of the corresponding phenothiazine cation-radicals. Kinetic investigation of the reactions between a series of methylphenothiazines and 4-methoxybenzenediazonium ion suggests a mechanism involving the rapid formation, at the heterocyclic nitrogen, of a cationic σ-complex which subsequently undergoes rate-determining homolysis. Correlations of the logarithms of the apparent second-order rate constants with the charge-transfer transition frequencies of the molecular π-complexes of the methylphenothiazines with 1,3,5-trinitrobenzene and with HMO coefficients of phenothiazine cation-radical itself, lead to conclusions concerning the nature of the rate-determining transition state.

Permittivities of the solid sulphates of phenothiazinic and 10-[3-(4-methyl-1-piperazinyl)-propyl]-phenothiazinic radical cations

The solid sulphates of phenothiazinic and 10-[3-(4-methyl-1-piperazinyl)propyl]-phenothiazinic radical cations were obtained by oxidation of phenothiazine and its corresponding N-substituted derivative with oxygen. The compositions, ESR spectra and permittivities of the compounds obtained have been measured. The values of static dielectric constants and ϵ ∞ as well as the dipole relaxation times for both compounds investigated are presented.

Heterocyclic free radicals. Part IV. Some reactions of phenothiazine, two derived radicals, and phenothiazin-5-ium ion

The reactions brought about when phenothiazine radical cation or phenothiazinium ion in acetonitrile is treated with aqueous solutions of various pH-values have been studied by spectroscopic methods. The proposed structure of a green dye which is formed under various conditions by the oxidation of phenothiazine has been confirmed. Evidence has been obtained about the modes of interconversion of phenothiazine and its oxidised derivatives.

Solvent Effect on the Photochemical Oxidation of Phenothiazine with Oxygen

Solvent Effect on the Photochemical Oxidation of Phenothiazine with Oxygen