title: Light-Tunable Generation of Singlet Oxygen and Nitric Oxide with a Bichromophoric Molecular Hybrid: a Bimodal Approach to Killing Cancer Cells.
abstract: The design, synthesis, photochemical properties, and biological evaluation of a novel photoactivatable bichromophoric conjugate are reported. The compound 1, [4-(4,4-difluoro-2,6-diiodo-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)-N-(3-((4-nitro-3-(trifluoromethyl)phenyl)amino)propyl)butanamide] combines a 2,6-diiodo-1,3,5,7-tetramethyl BODIPY derivative as singlet oxygen ((1) O2 ) photosensitizer and 4-nitro-3-(trifluoromethyl)aniline (NOPD) as nitric oxide (NO) photodonor, joined by an alkyl spacer. These two chromogenic units absorb in distinct regions of the visible spectrum, and their individual photochemical properties are conserved in the molecular conjugate. Irradiation of the bichromophoric conjugate with green light afforded (1) O2 in high quantum yields, whereas (1) O2 production was negligible with the use of blue light; under this latter condition, NO was released. Photogeneration of NO and cytotoxic (1) O2 can therefore be regulated by appropriately tuning the excitation light wavelength and intensity. Tested on melanoma cancer cells, this resulted in amplified photomortality relative to that of a structurally correlated model compound 2 [4-(4,4-difluoro-2,6-diiodo-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)-N-(3-(p-tolylamino)propyl)butanamide] deprived of the NO-release capacity. The cellular uptake of 1, evaluated by confocal fluorescence microscopy, showed that the product is localized in the cytoplasm.
authors.affiliation: Laboratory of Photochemistry, Department of Drug Sciences, University of Catania, 95125, Catania, Italy.
authors.forename: Aurore
authors.initials: A
authors.lastname: Fraix
authors.affiliation: Department of Science and Drug Technology, University of Torino, 10125, Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Blangetti
authors.affiliation: Department of Science and Drug Technology, University of Torino, 10125, Torino, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Guglielmo
authors.affiliation: Department of Science and Drug Technology, University of Torino, 10125, Torino, Italy.
authors.forename: Loretta
authors.initials: L
authors.lastname: Lazzarato
authors.affiliation: Laboratory of Photochemistry, Department of Drug Sciences, University of Catania, 95125, Catania, Italy.
authors.forename: Nino
authors.initials: N
authors.lastname: Marino
authors.affiliation: Department of Bio-Medical and Biotechnological Sciences, Physiology Division, University of Catania, 95125, Catania, Italy.
authors.forename: Venera
authors.initials: V
authors.lastname: Cardile
authors.affiliation: Department of Bio-Medical and Biotechnological Sciences, Physiology Division, University of Catania, 95125, Catania, Italy.
authors.forename: Adriana C E
authors.initials: AC
authors.lastname: Graziano
authors.affiliation: Istituto per la Sintesi Organica e la Fotoreattività-CNR, 40129, Bologna, Italy.
authors.forename: Ilse
authors.initials: I
authors.lastname: Manet
authors.affiliation: Department of Science and Drug Technology, University of Torino, 10125, Torino, Italy. roberta.fruttero@unito.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.affiliation: Department of Science and Drug Technology, University of Torino, 10125, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
authors.affiliation: Laboratory of Photochemistry, Department of Drug Sciences, University of Catania, 95125, Catania, Italy. ssortino@unict.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Sortino
mesh_terms: D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D008027:Light; D009369:Neoplasms / Q000473:pathology*; D009569:Nitric Oxide / Q000737:chemistry*; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology; D026082:Singlet Oxygen
chemical_list: D017319:Photosensitizing Agents; D026082:Singlet Oxygen; D009569:Nitric Oxide
keywords: bimodal therapy; light; nitric oxide; photodynamic therapy; radicals