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2,4,6-Triarylchalcogenopyrylium Dyes Related in Structure to the Antitumor Agent AA1 as in Vitro Sensitizers for the Photodynamic Therapy of Cancer

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journal contribution
posted on 03.09.1999, 00:00 by Kristi A. Leonard, Marina I. Nelen, Linda T. Anderson, Scott L. Gibson, Russell Hilf, Michael R. Detty
Cationic chalcogenopyrylium dyes 24 were synthesized in six steps from 4-(dimethylamino)phenylethyne (7), have absorption maxima in methanol of 594, 631, and 672 nm, respectively, and generate singlet oxygen with quantum yields [Φ(1O2)] of 0.020, 0.064, and 0.037, respectively. Dyes 24 are hydrolytically more stable than other chalcogenopyrylium dyes evaluated previously as sensitizers for photodynamic therapy. At 10 μM final concentration, all dyes 24 inhibited cytochrome c oxidase during irradiation of tumor mitochondrial suspensions treated with 10 μM dye. The degree of enzyme inhibition was abated in a reduced oxygen environment and in the presence of imidazole, a singlet oxygen trap. Superoxide dismutase, at a final concentration of 30 U, did not alter the photosensitized inhibition of mitochondrial cytochrome c oxidase by dyes 24. These data suggest that singlet oxygen may play a major role in the photosensitized inhibition of mitochondrial cytochrome c oxidase. Irradiation of R3230AC rat mammary adenocarcinoma cells in the presence of dyes 24 caused a significant loss in cell viability with thiopyrylium dye 2 displaying the greatest phototoxicity. Initial acute toxicity studies in vivo demonstrate that, at 10 mg/kg, none of the three dyes displayed overt toxicity.