A Molecular Hybrid for Mitochondria‐Targeted NO Photodelivery

Abstract

The design, synthesis, spectroscopic and photochemical properties, and biological evaluation of a novel molecular hybrid that is able to deliver nitric oxide (NO) into mitochondria are reported. This molecular conjugate unites a tailored o‐CF3‐p‐nitroaniline chromophore, for photo‐regulated NO release, and a rhodamine moiety, for mitochondria targeting, in the same molecular skeleton via an alkyl spacer. A combination of steady‐state and time‐resolved spectroscopic and photochemical experiments demonstrate that the two chromogenic units preserve their individual photophysical and photochemical properties in the conjugate quite well. Irradiation with violet light triggers NO release from the nitroaniline moiety and photoionization in the rhodamine center, which also retains considerable fluorescence efficiency. The molecular hybrid preferentially accumulates in the mitochondria of A549 lung adenocarcinoma cells where it induces toxicity at a concentration of 1 μm, exclusively upon irradiation. Comparative experiments, carried out with ad‐hoc‐synthesized model compounds, suggest that the phototoxicity observed at such a low concentration is probably not due to NO itself, but rather to the formation of the highly reactive peroxynitrite that is generated from the reaction of NO with the superoxide anion.

Tuning the Hydrophobicity of a Mitochondria‐Targeted NO Photodonor

“…Cytotoxicity was evaluated, 24 h after irradiation, by measuring the release of lactate dehydrogenase (LDH), which is sensitive to the loss of membrane integrity, and correlated well with the cell death. We have made use of the LDH release assay in our previous works on NO photodonors . The LDH assay was also performed here, as it is a sensitive index of irreversible cell damage leading to cell death, and to allow comparisons between the data obtained in the present work and in previous findings to be carried out .…”

“…We have made use of the LDH release assay in our previousw orks on NO photodonors. [15,27] The LDH www.chemmedchem.org assay was also performed here, as it is as ensitive index of irreversible cell damagel eading to cell death,a nd to allow comparisons between the data obtained in the present work and in previous findings to be carriedo ut. [32] Figure5 shows that the extent of cell death in both irradiated, untreated cells and in irradiated cells that had been treated with compound 2 is two times highert han that of non-irradiated cells.…”

“…The mitochondrial accumulation of NOPDs has therefore been proposed as an effective strategy for the design of new anticancer drugs. This approach has been created by linking the NOPDs to vectors that display high tropism for these organelles …”

“…This approach has been created by linking the NOPDs to vectors that display high tropism for these organelles. [11][12][13][14][15] NOPD class nitro derivatives that bear appropriate substituents at the o-a nd p-positions have received particular attention. Undert he action of violet light, these compounds undergo an itro-to-nitrite rearrangement, followed by OÀNO bond cleavage with consequent generation of NO andaphenoxy radicala nd, eventually,t he formation of nontoxicp henol compounds.…”

“…As a further development of our work on NOPDs that are structurally related to o ‐(trifluoro)methyl‐ p ‐nitroaniline, we have designed a series of new compounds in which N ‐[4‐nitro‐3‐(trifluoromethyl)phenyl]propane‐1,3‐diamine ( 1 , Scheme ), is linked through an amide bridge to alkyltriphenylphosphonium chains of variable length. This paper reports the synthesis, NO photorelease and partition coefficient (log P oct/w ), of these compounds as well as those of the acetyl derivative of 1 ( 2 , Scheme ), used as suitable reference model.…”