Free radicals phenothiazine

One of numerous examples of LOX-catalyzed cooxidation reactions is the oxidation and demethylation of amino derivatives of aromatic compounds. Oxidation of such compounds as 4-aminobiphenyl, a component of tobacco smoke, phenothiazine tranquillizers, and others is supposed to be the origin of their damaging effects including reproductive toxicity. Thus, LOX-catalyzed cooxidation of phenothiazine derivatives with hydrogen peroxide resulted in the formation of cation radicals [40]. Soybean LOX and human term placenta LOX catalyzed the free radical-mediated cooxidation of 4-aminobiphenyl to toxic intermediates [41]. It has been suggested that demethylation of aminopyrine by soybean LOX is mediated by the cation radicals and neutral radicals [42]. Similarly, soybean and human term placenta LOXs catalyzed N-demethylation of phenothiazines [43] and derivatives of A,A-dimethylaniline [44] and the formation of glutathione conjugate from ethacrynic acid and p-aminophenol [45,46],... 

The advantage of using free radical inhibitors to facilitate the copolymerization of a bisbenzocyclobutene with a bismaleimide was first noted in a patent to Bartmann [78]. Subsequent to this, Corley in a series of patents described some detailed experiments on the copolymerization of bisbenzocyclobutenes with bismaleimides both with and without the addition of a free radical inhibitor [33, 34]. The structures of the bisbenzocyclobutenes used in this study are shown in Fig. 33. The bismaleimide component that was used was a mixture of three different bismaleimides in the molar ratio shown in Fig. 34. The individual bisbenzocyclobutenes were blended at elevated temperature with varying amounts of the bismaleimide composition. In some of the experiments, the free radical inhibitor phenothiazine was added at a 0.5 mole % level. The various monomer mixtures were then copolymerized using one of the cure schedules described in Table 14. The copolymers were then physically characterized using a variety of techniques. Table 14 shows the results obtained from copolymers... 

A number of nucleophilic molecules can lose electrons in enzyme-catalyzed reactions (e.g., peroxidase). Thus hydrazines, amines, hydroquinones, phenothiazines, thiols, and aminophenols can form free radicals by this mechanism. 

Various phenothiazines (176) have been oxidized in CH3CN-Et4NC104 to a stable radical-cation (R = OCH3). The free radical resulting from deprotonation of the radical-cation gives in those cases where R = H, SCN, or t-Bu a C—N bond dimer, possibly 177272,2-73 [Eq. (107)]. 

Seven phenothiazines have been titrated with electrogenerated bromine in the range 0.1-3 mg with an average error of less than 1% [43]. The assay utilizes the oxidation of the phenothiazine in two one-electron steps to a cation-free radical and sulfoxide, respectively. 

IV. Free Radicals, Cations, and Charge-Transfer Complexes within the Phenothiazine Class... 

The species one has to deal with in the oxidation of phenothiazine are the radical forms (free radicals, semiquinones, ion radicals), the oxygenated and nonoxygenated phenazathionium cations, and the nonionic oxygenated forms, like the 5-oxide, 3-hydroxyphenothiazine, and phenothiazone. These species are interrelated by redox, proto-l3rtic, and hydrolytic processes, as shown in Scheme 1. 

Another incompletely elucidated problem is that of the configuration of the free radicals S and S". Malrieu and Pullman stated that S " is tetragonally folded and adopts the configuration H-intra (see Section 111, A, 2) the nonplanarity of the radical has been claimed as a possible cause of the disagreement between calculated and experimental ESR spectra. However, Lhoste and Tonnard, though considering that no definitive conclusion may be drawn in this question, appear to favor the hypothesis that the radical is nearly planar. Preliminary data about the phosphorescent triplet state of the phenothiazine molecule support this view. 

On thermal decomposition of 1, l,2,2,3,3,4,6,7,8,9-undecachloro-l, 2-dihydro-3i/-phenothiazine (25) the free radical octachloropheno-thiazinyl (26) has been obtained in the solid state by Bodea and Silberg. ° Thermogravimetric and elemental analysis data confirm the following reaction ... 

Under different conditions of thermal decomposition the concentration of the free radical remains approximately constant at about 30%, that is, one unpaired spin for three phenothiazine moieties. The IR spectrum of the thermal decomposition product shows that no N—H bond is present, and on boiling in aniline the product is quantitatively converted into octachlorophenothiazine. This is strong evidence for a mixture of 30% free radical and 70% dimer, hexadeca-chloro-10,10 -biphenothiazine. 

At very low pH thionol semiquinone, that is, 3,7-dihydroxy-S" may be prepared. This is the free radical with the highest oxidation state so far encountered within the phenothiazine class. 

Chignell CF, Motten AG, Buettner GR. Photoinduced free radicals from chlorpromazine and related phenothiazines relationship to phenothiazine-induced photosensitization. Env Health Perspect 1985 64 103-110. 

Asmus, K.-D., Bahnemann, D., Monig, J., Searle, A., and Wilson, R.L. (1979) Electrophilic free radicals and phenothiazine a pulse radiolysis study, in Edwards, H.E., Navarat-nam, S., Parsons, B.J., and Phillips, G.O. (Eds.), Radiation Biology and Chemistry Research and Development, Amsterdam, Elservier, pp. 39 -7. 

Gutierrez-Correa J, Krauth-Siegel RL, Stoppani AO. Phenothiazine radicals inactivate Trypanosoma cruzi dihydrolipoamide dehydrogenase enzyme protection by radical scavengers. Free Radic Res 2003 37 281-91. 

Like other phenothiazines, fluphenazine hydrochloride reacts with ceric sulfate, first by forming a red-colored semiquinone free radical (420 mp), followed by formation of the colorless... 

Controlled potential electrolysis has been applied for the coulometric quantitative determination of tri-flupromazine and other phenothiazines. Depending on the oxidation potential (anode potential with respect to S.E.C (standard calomel electrode)) and acid strength triflupromazine was oxidized to the free radical (Ox, Pot. + 0,65 12N H2SO4) or the sulfoxide (Ox. Pot. 

A role for norepinephrine systems in schizophrenic pathology has been suggested (Mason, 1983) and may lead to a different therapy. The red free-radicals to which phenothiazines are readily oxidized (Borg and Cotzias, 1962) do not appear to play any part in their neuroleptic action. 

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