In vitro photodynamic properties of chalcogenopyrylium analogues of the thiopyrylium antitumor agent AA1.

Abstract

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.

• Authors: Nancy K Brennan, Jonathan P Hall, Sherry R Davies, Sandra O Gollnick, Allan R Oseroff, Scott L Gibson, Russell Hilf, Michael R Detty
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 45 Issue 23 Pg. 5123-35 (Nov 07 2002) ISSN: 0022-2623 [Print] United States
• PMID: 12408723 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Aniline Compounds
• Chalcogens
• Coloring Agents
• Photosensitizing Agents
• Pyrans
• Thiophenes
• 2,6-bis(4-aminophenyl)-4-(4-(dimethylamino)phenyl)thiopyrylium
• Sulfur
• Electron Transport Complex IV
• Selenium
• Tellurium

Topics

• Aniline Compounds (chemistry)
• Animals
• Chalcogens (chemistry)
• Coloring Agents
• Darkness
• Electron Transport Complex IV (metabolism)
• Lethal Dose 50
• Light
• Mice
• Mitochondria (metabolism)
• Photochemotherapy
• Photosensitizing Agents (chemical synthesis, pharmacology, radiation effects)
• Pyrans (chemical synthesis, pharmacology, radiation effects)
• Selenium (chemistry)
• Solubility
• Sulfur (chemistry)
• Tellurium (chemistry)
• Thiophenes (chemistry)
• Tumor Cells, Cultured