title: Roles of free radicals in type 1 phototherapeutic agents: aromatic amines, sulfenamides, and sulfenates.
abstract: Detailed analyses of the electron spin resonance (ESR) spectra, cell viability, and DNA degradation studies are presented for the photolyzed Type I phototherapeutic agents: aromatic amines, sulfenamides, and sulfenates. The ESR studies provided evidence that copious free radicals can be generated from these N-H, N-S, and S-O containing compounds upon photoirradiation with UV/visible light. The analyses of spectral data allowed us to identify the free radical species. The cell viability studies showed that these agents after exposure to light exert cytotoxicity to kill cancer cells (U937 leukemia cell lines HTC11, KB, and HT29 cell lines) in a dosage- and time-dependent manner. We examined a possible pathway of cell death via DNA degradation by a plasmid cleavage assay for several compounds. The effects of photosensitization with benzophenone in the presence of oxygen were examined. The studies indicate that planar tricyclic amines and sulfenamides tend to form π-electron delocalized aminyl radicals, whereas nonplanar ones tend to yield nitroxide radicals resulting from the recombination of aminyl radicals with oxygen. The ESR studies coupled with the results of cell viability measurements and DNA degradation reveal that planar N-centered radicals can provide higher potency in cell death and allow us to provide some insights on the reaction mechanisms. We also found the formation of azatropylium cations possessing high aromaticity derived from azepines can facilitate secondary electron transfer to form toxic O2(•-) radicals, which can further exert oxidative stress and cause cell death.
authors.affiliation: Department of Chemistry, Washington University , St. Louis, Missouri 63130, United States.
authors.forename: Tien-Sung
authors.initials: TS
authors.lastname: Lin
authors.forename: Raghavan
authors.initials: R
authors.lastname: Rajagopalan
authors.forename: Yuefei
authors.initials: Y
authors.lastname: Shen
authors.forename: Sungho
authors.initials: S
authors.lastname: Park
authors.forename: Amruta R
authors.initials: AR
authors.lastname: Poreddy
authors.forename: Bethel
authors.initials: B
authors.lastname: Asmelash
authors.forename: Amolkumar S
authors.initials: AS
authors.lastname: Karwa
authors.forename: John-Stephen A
authors.initials: JS
authors.lastname: Taylor
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000737:chemistry / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D007624:KB Cells; D015394:Molecular Structure; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013434:Sulfenic Acids / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D020298:U937 Cells
chemical_list: D000588:Amines; D005609:Free Radicals; D017319:Photosensitizing Agents; D013434:Sulfenic Acids; D004247:DNA