Tuning the Hydrophobicity of a Mitochondria‐Targeted NO Photodonor

A few compounds in which the nitric oxide (NO) photodonor N‐[4‐nitro‐3‐(trifluoromethyl)phenyl]propane‐1,3‐diamine is joined to the mitochondria‐targeting alkyltriphenylphosphonium moiety via flexible spacers of variable length were synthesized. The lipophilicity of the products was evaluated by mea...

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Bibliographic Details
Published in:ChemMedChem 2018-06, Vol.13 (12), p.1238-1245
Main Authors: Sodano, Federica, Rolando, Barbara, Spyrakis, Francesca, Failla, Mariacristina, Lazzarato, Loretta, Gazzano, Elena, Riganti, Chiara, Fruttero, Roberta, Gasco, Alberto, Sortino, Salvatore
Format: Article
Language:English
Subjects:
Accumulation
Adenocarcinoma
Conformation
Hydrophobicity
Irradiation
Light irradiation
Lipophilicity
Lung cancer
Lungs
Mathematical analysis
Mitochondria
Molecular chains
Molecular dynamics
Nitric oxide
Octanol
phosphonium salts
photoactivation
Radiation
targeted therapy
Toxicity
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Summary:A few compounds in which the nitric oxide (NO) photodonor N‐[4‐nitro‐3‐(trifluoromethyl)phenyl]propane‐1,3‐diamine is joined to the mitochondria‐targeting alkyltriphenylphosphonium moiety via flexible spacers of variable length were synthesized. The lipophilicity of the products was evaluated by measuring their partition coefficients in n‐octanol/water. The obtained values, markedly lower than those calculated, are consistent with the likely collapsed conformation assumed by the compounds in solution, as suggested by molecular dynamics simulations. The capacity of the compounds to release NO under visible light irradiation was evaluated by measuring nitrite production by means of the Griess reaction. The accumulation of compounds in the mitochondria of human lung adenocarcinoma A549 cells was assessed by UPLC–MS. Interestingly, compound 13 [(9‐((3‐((4‐nitro‐3‐(trifluoromethyl)phenyl)amino)propyl)amino)‐9‐oxononyl) triphenylphosphonium bromide] displayed both the highest accumulation value and high toxicity toward A549 cells upon irradiation‐mediated NO release in mitochondria. Targeting mitochondria: A few NO‐photodonor alkyltriphenylphosphonium compounds were synthesized to modulate their lipophilicity and capacity to release NO under the control of light irradiation. Compound 13 showed the highest tendency to assume a globular structure. It exhibited extended accumulation in the mitochondria of human lung adenocarcinoma A549 cells and displayed high toxicity upon irradiation‐mediated NO release in mitochondria.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201800088