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 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.

[1]  B. Rolando,et al.  Folate‐targeted liposomal nitrooxy‐doxorubicin: An effective tool against P‐glycoprotein‐positive and folate receptor‐positive tumors , 2018, Journal of controlled release : official journal of the Controlled Release Society.

[2]  B. Rolando,et al.  A Molecular Hybrid for Mitochondria‐Targeted NO Photodelivery , 2018, ChemMedChem.

[3]  J. Joseph,et al.  Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications. , 2017, Chemical reviews.

[4]  Junjie Fu,et al.  Nitric Oxide Donor-Based Cancer Therapy: Advances and Prospects. , 2017, Journal of medicinal chemistry.

[5]  L. García-Ledo,et al.  Overexpression of the ATPase Inhibitory Factor 1 Favors a Non-metastatic Phenotype in Breast Cancer , 2017, Frontiers in oncology.

[6]  B. Rolando,et al.  Light-Regulated NO Release as a Novel Strategy To Overcome Doxorubicin Multidrug Resistance. , 2017, ACS medicinal chemistry letters.

[7]  J. Chipuk,et al.  Mitochondrial dynamics as regulators of cancer biology , 2017, Cellular and Molecular Life Sciences.

[8]  Shana O. Kelley,et al.  Mitochondria-Targeted Doxorubicin: A New Therapeutic Strategy against Doxorubicin-Resistant Osteosarcoma , 2016, Molecular Cancer Therapeutics.

[9]  Loretta Lazzarato,et al.  Light‐Tunable Generation of Singlet Oxygen and Nitric Oxide with a Bichromophoric Molecular Hybrid: a Bimodal Approach to Killing Cancer Cells , 2016, ChemMedChem.

[10]  A. Weeraratna,et al.  PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion , 2015, Proceedings of the National Academy of Sciences.

[11]  Fang Zeng,et al.  A mitochondrial-targeting and NO-based anticancer nanosystem with enhanced photo-controllability and low dark-toxicity. , 2015, Journal of materials chemistry. B.

[12]  E. Gazzano,et al.  Two repeated low doses of doxorubicin are more effective than a single high dose against tumors overexpressing P-glycoprotein. , 2015, Cancer letters.

[13]  Aurore Fraix,et al.  Photoactivable platforms for nitric oxide delivery with fluorescence imaging. , 2015, Chemistry, an Asian journal.

[14]  John F. Callan,et al.  Carbon quantum dot-NO photoreleaser nanohybrids for two-photon phototherapy of hypoxic tumors. , 2015, Chemical communications.

[15]  Takayoshi Suzuki,et al.  Visible light-induced nitric oxide release from a novel nitrobenzene derivative cross-conjugated with a coumarin fluorophore. , 2014, Bioorganic & medicinal chemistry letters.

[16]  V. Cardile,et al.  A multi-photoresponsive molecular-hybrid for dual-modal photoinactivation of cancer cells , 2014 .

[17]  Fang Zeng,et al.  Preparation of a mitochondria-targeted and NO-releasing nanoplatform and its enhanced pro-apoptotic effect on cancer cells. , 2014, Small.

[18]  P. Ford.  Photochemical delivery of nitric oxide. , 2013, Nitric oxide : biology and chemistry.

[19]  D Ghigo,et al.  The Role of Iron Impurities in the Toxic Effects Exerted by Short Multiwalled Carbon Nanotubes (MWCNT) in Murine Alveolar Macrophages , 2013, Journal of toxicology and environmental health. Part A.

[20]  B. Nawrot,et al.  High Cytotoxic Activity of Phosphonium Salts and Their Complementary Selectivity towards HeLa and K562 Cancer Cells: Identification of Tri-n-butyl-n-hexadecylphosphonium bromide as a Highly Potent Anti-HeLa Phosphonium Salt , 2012, ChemistryOpen.

[21]  David Kessel,et al.  Photodynamic therapy of cancer: An update , 2011, CA: a cancer journal for clinicians.

[22]  Takayoshi Suzuki,et al.  Photoinduced nitric oxide release from a nitrobenzene derivative in mitochondria. , 2011, Chemistry.

[23]  Takayoshi Suzuki,et al.  A novel mitochondria-localizing nitrobenzene derivative as a donor for photo-uncaging of nitric oxide. , 2011, Bioorganic & medicinal chemistry letters.

[24]  P. Mascharak,et al.  Photoactive ruthenium nitrosyls as NO donors: how to sensitize them toward visible light. , 2011, Accounts of chemical research.

[25]  S. Sortino.  Light-controlled nitric oxide delivering molecular assemblies. , 2010, Chemical Society reviews.

[26]  P. Wipf,et al.  Mitochondria as a target in treatment , 2010, Environmental and molecular mutagenesis.

[27]  Min Zhang,et al.  Targeting the L-arginine-nitric oxide pathway for cancer treatment. , 2010, Current pharmaceutical design.

[28]  C. Riganti,et al.  Geranylgeraniol prevents the cytotoxic effects of mevastatin in THP‐1 cells, without decreasing the beneficial effects on cholesterol synthesis , 2009, British journal of pharmacology.

[29]  Alexis D. Ostrowski,et al.  Metal complexes as photochemical nitric oxide precursors: potential applications in the treatment of tumors. , 2009, Dalton transactions.

[30]  S. Sortino,et al.  Amplified nitric oxide photorelease in DNA proximity. , 2008, Chemical communications.

[31]  Carsten Kutzner,et al.  GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. , 2008, Journal of chemical theory and computation.

[32]  P. Ford.  Polychromophoric metal complexes for generating the bioregulatory agent nitric oxide by single- and two-photon excitation. , 2008, Accounts of chemical research.

[33]  S. Petralia,et al.  Photodelivery of nitric oxide from water-soluble platinum nanoparticles. , 2007, Journal of the American Chemical Society.

[34]  M. Parrinello,et al.  Canonical sampling through velocity rescaling. , 2007, The Journal of chemical physics.

[35]  Takayoshi Suzuki,et al.  Photoinduced nitric oxide release from nitrobenzene derivatives. , 2005, Journal of the American Chemical Society.

[36]  Jorge D. Erusalimsky,et al.  Does nitric oxide modulate mitochondrial energy generation and apoptosis? , 2002, Nature Reviews Molecular Cell Biology.

[37]  J. Modica-Napolitano,et al.  Delocalized lipophilic cations selectively target the mitochondria of carcinoma cells. , 2001, Advanced drug delivery reviews.

[38]  J. Lancaster,et al.  Nitric oxide: a new paradigm for second messengers. , 1995, Journal of medicinal chemistry.

[39]  J. Kerwin,et al.  The arginine‐nitric oxide pathway: A target for new drugs , 1994, Medicinal research reviews.

[40]  Aurore Fraix,et al.  Phototherapeutic Release of Nitric Oxide with Engineered Nanoconstructs. , 2016, Topics in current chemistry.

[41]  Peng Huang,et al.  Targeting cancer cell mitochondria as a therapeutic approach. , 2013, Future medicinal chemistry.

[42]  Guy C. Brown.  Nitric oxide and mitochondria. , 2007, Frontiers in bioscience : a journal and virtual library.