title: 2,4,6-triarylchalcogenopyrylium dyes related in structure to the antitumor agent AA1 as in vitro sensitizers for the photodynamic therapy of cancer.
abstract: 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 yields [Phi((1)O(2))] of 0.020, 0.064, and 0.037, respectively. Dyes 2-4 are hydrolytically more stable than other chalcogenopyrylium dyes evaluated previously as sensitizers for photodynamic therapy. At 10 microM final concentration, all dyes 2-4 inhibited cytochrome c oxidase during irradiation of tumor mitochondrial suspensions treated with 10 microM 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 2-4. 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 2-4 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.
authors.affiliation: Departments of Chemistry and Medicinal Chemistry, State University of New York at Buffalo, Buffalo, New York 14260, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Leonard
authors.forename: M I
authors.initials: MI
authors.lastname: Nelen
authors.forename: L T
authors.initials: LT
authors.lastname: Anderson
authors.forename: S L
authors.initials: SL
authors.lastname: Gibson
authors.forename: R
authors.initials: R
authors.lastname: Hilf
authors.forename: M R
authors.initials: MR
authors.lastname: Detty
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000628:therapy; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D004396:Coloring Agents / Q000737:chemistry / Q000627:therapeutic use*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D005260:Female; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D015674:Mammary Neoplasms, Animal / Q000201:enzymology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D013054:Spectrophotometry, Atomic; D014407:Tumor Cells, Cultured
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004396:Coloring Agents; D016566:Organoselenium Compounds; D017319:Photosensitizing Agents; D003576:Electron Transport Complex IV