In Vitro Photodynamic Properties of Chalcogenopyrylium Analogues of the Thiopyrylium Antitumor Agent AA1

Several series of chalcogenopyrylium dyes were prepared with one or two 4-anilino substituents at the 2- and 6-positions and with phenyl, 4-N,N-dimethylanilino, or 4-(N-morphilino)phenyl substituents at 2- and/or 4-positions. The dye series are all related in structure to AA1, a thiopyrylium dye that targets mitochondria. The chalcogenopyrylium nuclei included sulfur, selenium, and tellurium at the 1-position. Key intermediates in the dye synthesis were the corresponding Delta-4H-chalcogenopyran-4-ones. All of the dyes of this study were evaluated for dark and phototoxicity toward Colo-26 cells in vitro. There was no correlation of dark toxicity with either the reduction potential of the chalcogenopyrylium dye or the n-octanol/water partition coefficient, log P. Several of the dyes of this study (thiopyrylium dyes 1-S and 13-S, selenopyrylium dyes 1-Se, 2-Se, 3-Se, 4-Se, 13-Se, 14-Se, and 27-Se, and telluropyrylium dye 13-Te) showed added phototoxicity upon irradiation. Dyes with the highest therapeutic ratio as measured by dark toxicity/phototoxicity (15 J cm(-2) of 360-800-nm light) had values of log P of 1.0-1.2. Studies of cytochrome c oxidase activity in whole R3230AC cells suggested that dyes 1-S and 3-Se, with values of log P of 2.2 and 1.7, respectively, were localized in the mitochondria. Cytocrome c oxidase activity in whole cells was inhibited by 1-S and 3-Se in the dark. Chalcogenopyrylium dyes 2-Se, 4-Se, 13-Te, and 14-Se inhibited whole-cell cytochrome c oxidase activity only following irradiation, which suggests that these dyes relocalized to mitochondria following irradiation.