Photochemically Generated Stable Cation Radical of Phenothiazine Aggregates in Mildly Acid Buffered Solutions Tiago Rodrigues, † Carolina G. dos Santos, † Alessandra Riposati, | Leandro R. S. Barbosa, § Paolo Di Mascio, ‡ Rosangela Itri, § Maurı ´cio S. Baptista, ‡ Otaciro R. Nascimento, | and Iseli L. Nantes †, * Centro Interdisciplinar de InVestigac ¸ a ˜ o Bioquı ´micasCIIB, UniVersidade de Mogi das CruzessUMC, Mogi das CruzessSP, Brazil, Depto de Bioquı ´mica, Instituto de Quı ´mica, UniVersidade de Sa ˜ o PaulosUSP, Sa ˜ o PaulosSP, Brazil, Instituto de Fı ´sica, UniVersidade de Sa ˜ o PaulosUSP, Sa ˜ o PaulosSP, Brazil, and Instituto de Fı ´sica, UniVersidade de Sa ˜ o PaulosUSP, Sa ˜ o CarlossSP, Brazil ReceiVed: January 25, 2006; In Final Form: May 3, 2006 This work characterizes, for the first time, the photochemical behavior of the antipsychotic drugs thioridazine (TR), trifluoperazine (TFP), and fluphenazine (FP) influenced by the aggregation state of the molecules. Samples of monomeric and aggregated forms of phenothiazines were submitted to 20 min of irradiation at 254 nm for intervals of 1, 5, 10, 15, 20, or 25 days. In high phenothiazine concentrations, the irradiation led to the appearance of absorbance bands in the visible region peaking at 633 nm for TR and 509 nm for FP and TFP. In the dark, at room temperature and at 4 °C, these bands disappeared, after ∼15 and ∼60 min, respectively, but reappeared after a new irradiation session. These visible bands were assigned to stable cation radicals that were characterized by direct EPR measurements and by flash photolysis. Photogenerated stable cation radicals in the phenothiazine aggregates at room temperature are formed probably due to the stacking of the thiazine phenyl moieties. For the monomeric forms of phenothiazines, the spectral changes observed during the irradiation suggested the formation of sulfoxide and hydroxylated derivates. Oxidized derivates were detected by mass spectrometry of the aggregated forms of phenothiazines (>100 μM) only in the samples irradiated for more than 20 days. In contrast, monomeric phenothiazines were totally converted to the oxidized forms after 20 min of irradiation. Surface tension measurements of phenothiazines revealed that, in concentrations above 100 μM, the drugs formed aggregates. In the case of TR, small-angle X-ray scattering measurements indicated that this compound forms large lamellar-like aggregates in aqueous solutions. Introduction Phenothiazine derivatives have been the focus of several biological, chemical, physical-chemical, and photochemical studies due to their pharmaceutical properties and applications. 1,2 Particularly, the photochemical behavior of phenothiazines has gained interest as the compounds containing a phenothiazine moiety may promote photosensitizing effects in patients under therapy with these drugs. 3,4 Literature data reveal that the photophysics and photochem- istry of phenothiazine compounds are influenced by the sub- stituents at positions 1 and 2 (Chart 1), the nature of the solvent, and the excitation energy. 5,6 Under irradiation, phenothiazines can attain the first singlet excited state S 1 or S n , depending on the energy of excitation and the solvent. 7 The formation of the singlet excited state S n can occur by a biphotonic or a monophotonic absorption process. The decay of the singlet excited states can occur via internal conversion (S n f S 1 and S 1 f S 0 plus heat), fluorescence (S 1 f S 0 plus hν), and intersystem crossing (S 1 f T 1 or S 2 f T 2 and T 2 fT 1 , via internal conversion). The decay of the first triplet excited state can occur via phosphorescence. Phenothiazine derivates show comparatively weak values of quantum yields of fluorescence, but their quantum yields of phosphorescence are always better than 0.3 and sometimes very near 1. Therefore, it can be deduced that the quantum yields of the intersystem crossing (IC) for phenothiazine derivates are very near 1. 8 Besides the phosphorescence, two mechanisms can also answer for the triplet-state deactivation: energy transfer to molecular oxygen, which leads to the generation of 1 O 2 (singlet molecular oxygen), and photoionization processes. The photoionization of phenothiazine derivates (PTH) could generate the cation radical and solvated electron (eq 1) or the neutral phenothiazine and hydrogen radicals (eqs 2 and 3). The photoionization of phenothiazines via the singlet mani- fold, yielding the cation radical, in competition with intersystem crossing and bond cleavage, has been described by several authors. 7,9,10 The cation radical can react with molecular oxygen, generating a phenothiazine sulfoxide derivate. 11 The ability of some phenothiazine derivates to aggregate in micellar structures has been presented in the literature. 12 * To whom correspondence should be addressed. Phone: +55-11-4798- 7103. Fax: +55-11-4798-7102. E-mail: ilnantes@umc.br. † Universidade de Mogi das Cruzes. ‡ Instituto de Quı ´mica, Universidade de Sa ˜o Paulo. § Instituto de Fı ´sica, Universidade de Sa ˜o PaulosUSP, Sa ˜o Paulo. | Instituto de Fı ´sica, Universidade de Sa ˜o PaulosUSP, Sa ˜o Carlos. PTH 9 8 hν PTH* f PTH• + + e - s (1) PTH 9 8 hν PTH* f PT•+ H• (monophotonic homolytic cleavage) (2) PTH 9 8 hν PTH* f PTH• + + e - s f PT•+ H• (thermal or photolytic deprotonation of PTH• + ) (3) 12257 J. Phys. Chem. B 2006, 110, 12257-12265 10.1021/jp0605404 CCC: $33.50 © 2006 American Chemical Society Published on Web 06/08/2006