Primary steps of the photochemical reactions of 2-cyano-10-(3-[dimethylamino, N-oxide]-2-methylpropyl)-5-oxide-phenothiazine, the photoproduct of cyamemazine, a phototoxic neuroleptic: comparison with the sulfoxide

Abstract

The UVA-absorbing photoproduct resulting from the oxidation of the sulfur atom and of the side chain nitrogen of the phototoxic drug cyamemazine (CMZ) (2-cyano-10-(3-[dimethylamino]-2 methylpropyl)-phenothiazine) is a potent photodynamic photosensitizer. The photophysical and photochemical properties of this photoproduct (P) (2-cyano-10-(3-[dimethylamino, N-oxide]-2-methylpropyl)-5-oxide-phenothiazine)) have been investigated in neutral buffered aqueous solutions and in ethanol and compared to those of the sulfoxide (S) (2-cyano-10-(3-[dimethylamino]-2 methylpropyl)-5-oxide-phenothiazine), a CMZ oxidation product of cells. The fluorescence quantum yield (Φ_F) of P is 0.25 and 0.21 in pH 7 phosphate buffer and ethanol, respectively. By contrast, S (Φ_F = 0.14 in buffer) is practically unfluorescent in alcohol. In buffer, the fluorescence lifetimes of P and S are 10.5 and 11.8 ns, respectively. The transient absorbance of the first excited triplet state (³P₁) with a characteristic absorption band peaking at 660 nm (ε = 5 300 M⁻¹ cm⁻¹) has been observed by 355 nm laser flash spectroscopy of deaerated phosphate buffer or ethanol solutions. In buffer, the ³P₁ lifetime is 0.5 µs. The energy transfer which occurs from the ³P₁ to naproxen suggests that the ³P₁ energy is greater than 62 kcal mol⁻¹. Triplet quenching by dioxygen occurs at rate 2.3 × 10⁹ M⁻¹ s⁻¹. With the triplet benzophenone as actinometer, the ³P₁ formation quantum yield is found to be 0. 40 in buffer. The ³P₁ state is quenched by ethanol and 2-propanol with bimolecular reaction rate constants of 1.6 and 2.4 × 10⁶ M⁻¹ s⁻¹, respectively. In buffer, P and S triplet states react with tryptophan, indole and cysteine at rate constants of the order of 10⁹ M⁻¹ s⁻¹ for Trp and indole and 10⁸ M⁻¹ s⁻¹ for Cys.