2,4,6-Triarylchalcogenopyrylium dyes related in structure to the antitumoragent AA1 as in vitro sensitizers for the photodynamic therapy of cancer

Cationic chalcogenopyrylium dyes 2-4 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 yi elds [Phi(O-1(2))] of 0.020, 0.064, and 0.037, respectively. Dyes 2-4 are h ydrolytically more stable than other chalcogenopyrylium dyes evaluated prev iously as sensitizers for photodynamic therapy. At 10 mu M final concentrat ion, all dyes 2-4 inhibited cytochrome c oxidase during irradiation of tumo r mitochondrial suspensions treated with 10 mu M dye. The degree of enzyme inhibition was abated in a reduced oxygen environment and in the presence o f imidazole, a singlet oxygen trap. Superoxide dismutase, at a final concen tration of 30 U, did not alter the photosensitized inhibition of mitochondr ial cytochrome c oxidase by dyes 2-4. These data suggest that singlet oxyge n may play a major role in the photosensitized inhibition of mitochondrial cytochrome c oxidase. Irradiation of R3230AC rat: mammary adenocarcinoma ce lls in the presence of dyes 2-4 caused a significant loss in cell viability with thiopyrylium dye 2 displaying the greatest phototoxicity. Initial acu te toxicity studies in vivo demonstrate that, at 10 mg/kg, none of the thre e dyes displayed overt toxicity.