Excited-state Properties and In Vitro Phototoxicity Studies of Three Phenothiazine Derivatives¶

Abstract

This work concerns a combined photophysical, photochemical and photobiological study of three drugs (psychotherapeutic agents) of the phenothiazine series: perphenazine, fluphenazine hydrochloride and thioridazine hydrochloride. The excited-state properties were first investigated by stationary and time-resolved fluorimetry and by laser flash photolysis. The spectral description was assisted by quantum-mechanical calculations with the INDO/1-CI method. In organic media the lowest excited singlet state was found to decay by fluorescence (small quantum yield) and mainly by intersystem crossing to the lowest triplet state, which is responsible for oxygen photosensitization (high yields of singlet oxygen production) and photodegradation. A further decay pathway in aqueous solutions was the photoionization process, which led to the formation of the phenothiazine radical cations and the solvated electron. After the preliminary study of the photobehavior in organic solvents and in water, the phototoxicity of the three drugs was investigated on various biological substrates through a series of in vitro assays under UVA irradiation. Photohemolysis of mouse erythrocytes and phototoxicity on cultured murine fibroblasts were observed for all three compounds. Lipid photoperoxidation was then investigated using linoleic acid as the unsaturated lipid model and isolated red blood cell membranes. The drug-induced photodamage was also evaluated on proteins by measuring the photosensitizing cross-linking in erythrocyte ghosts. The combined approach proved to be useful in understanding the mechanism by which these phenothiazine derivatives induce skin photosensitization. In particular, the photophysical properties of the compounds under investigation and the results of the study on their phototoxicity are in agreement with a mechanism that involves the radical cation of the drugs as a main intermediate.

Photosensitization of DNA Strand Breaks by Three Phenothiazine Derivatives

“…To reach a deeper insight on the reaction mechanism, laser flash photolysis experiments were carried out on phenothiazines in PBS in the presence of GMP and DNA. As already reported (12), direct excitation of the drugs in the absence of additives produced three transients assigned to the lower triplet state of phenothiazines (λ max ) 480 nm), to their radical cation (λ max ) 520, 530, and 630 nm for PP, FP, and TR, respectively), and to the solvated electron (λ max ) 710 nm) formed within the laser pulse. Figure 8 shows the timeresolved absorption spectra of the drugs in the presence of GMP.…”

“…The absorption band at ca. 500 nm is assigned to the lowest triplet state of PP by comparison with previously reported data (12); instead, the longer-lived transient, which absorbs at ca. 390 and 540 nm, is assigned to the cation radicals PP •+ (12).…”

“…500 nm is assigned to the lowest triplet state of PP by comparison with previously reported data (12); instead, the longer-lived transient, which absorbs at ca. 390 and 540 nm, is assigned to the cation radicals PP •+ (12). The short-lived absorption at 600 nm was then attributed to the anion radical of DNA basis formed by electron transfer from the singlet excited state of PP (in fact, its absorption was produced within the laser pulse).…”

An experimental and theoretical study on the photophysical properties of methylene green

“…The f F are always small (<0.1) and the s F are in the subnanosecond time scale in all the media studied. The small observed fluorescence quantum yields are typical of phenothiazines dyes [56]. Both f F and s F have a tendency to decrease with increasing solvent polarity.…”

Thioridazine Pharmacokinetic-Pharmacodynamic Parameters “Wobble” during Treatment of Tuberculosis: a Theoretical Basis for Shorter-Duration Curative Monotherapy with Congeners

“…Rifampin was initially diluted in dimethyl sulfoxide and then back diluted in broth to make a final dimethyl sulfoxide concentration of Ͻ1% as described in the past (24). All THI experiments were performed so as to avoid direct light, since phenothiazines are highly potent photosensitizers that cause photodynamic damage to cells, which would lead to exaggerated efficacy (31)(32)(33). All drugs were prepared fresh for each experiment.…”