Spin Trapping and Cytoprotective Properties of Fluorinated Amphiphilic Carrier Conjugates of Cyclic versus Linear Nitrones

Durand, Grégory; Prosak, Robert A.; Han, Yu; Ortial, Stéphanie; Rockenbauer, Antal; Pucci, Bernard; Villamena, Frederick A.

doi:10.1021/tx900114v

Cited by 22 publications

(45 citation statements)

References 82 publications

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“…Finally, after purification by aqueous size exclusion chromatography, the Zempl en de-O-acetylation procedure led to compounds 11 and 12. The amphiphilic nitrones 11 and 12, as well as their acetylated derivatives 9 and 10, were fully characterized by 1 H, 13 C, 19 F, DEPT, and HMQC NMR as well as mass spectrometry (ESIþ). The purity of 11 and 12 was confirmed by C18 reverse phase HPLC and was higher than 95% (see Supporting Information).…”

Section: Chemistrymentioning

confidence: 99%

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Amphiphilic Amide Nitrones: A New Class of Protective Agents Acting as Modifiers of Mitochondrial Metabolism

et al. 2010

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Our group has demonstrated that the amphiphilic character of alpha-phenyl-N-tert-butyl nitrone based agents is a key feature in determining their bioactivity and protection against oxidative toxicity. In this work, we report the synthesis of a new class of amphiphilic amide nitrones. Their hydroxyl radical scavenging activity and radical reducing potency were shown using ABTS competition and ABTS(+) reduction assays, respectively. Cyclic voltammetry was used to investigate their redox behavior, and the effects of the substitution of the PBN on the charge density of the nitronyl atoms, the electron affinity, and the ionization potential were computationally rationalized. The protective effects of amphiphilic amide nitrones in cell cultures exposed to oxidotoxins greatly exceeded those exerted by the parent compound PBN. They decreased electron and proton leakage as well as hydrogen peroxide formation in isolated rat brain mitochondria at nanomolar concentration. They also significantly enhanced mitochondrial membrane potential. Finally, dopamine-induced inhibition of complex I activity was antagonized by pretreatment with these agents. These findings indicate that amphiphilic amide nitrones are much more than just radical scavenging antioxidants but may act as a new class of bioenergetic agents directly on mitochondrial electron and proton transport.

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Section: Chemistrymentioning

confidence: 99%

“…Calculated Electron Affinities, Ionization Potentials, and Charge Densities of the Nitronyl Atoms of13,12,11, and PBN at the…”

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confidence: 99%

Amphiphilic Amide Nitrones: A New Class of Protective Agents Acting as Modifiers of Mitochondrial Metabolism

et al. 2010

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“…These amino-acid drug conjugates were then used as prodrugs to treat cancer cells. Furthermore, the development of amino acid-antioxidant conjugates and amino acid-anti-angiogenic conjugates were also recently reported in the literature (Ortial et al 2006;Durand et al 2009;Contino-Pépin et al 2009). Hence, amino-acid derivatives are a promising avenue, which must be further exploited in the search for new drug candidates.…”

Section: Introductionmentioning

confidence: 91%

“…Indeed, it is reported that m-tyrosine is significantly more phytotoxic than its structural isomers o-and p-tyrosine (Bertin et al 2007). Furthermore, it is reported that phenolic compounds exhibiting antioxidant properties can contribute to the destruction of cancer cells (Durand et al 2009). The slightly greater activity observed for the m-tyrosine regioisomer might be explained by these factors being more important for the meta isomer compared to the ortho and para isomers.…”

Section: In Vitro Biological Activitymentioning

confidence: 99%

SAR study of tyrosine–chlorambucil hybrid regioisomers; synthesis and biological evaluation against breast cancer cell lines

et al. 2011

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Amino acids were transformed and coupled to chlorambucil, a well-known chemotherapeutic agent, in an attempt to create new anticancer drugs with selectivity for breast cancer cells. Among the amino acids available, tyrosine was selected to act as an estrogenic ligand. It is hypothesized that tyrosine, which shows some structural similitude with estradiol, could possibly mimic the natural hormone and, subsequently, bind to the estrogen receptor. In this exploratory study, several tyrosine-drug conjugates have been designed. Thus, ortho-, meta- and para-tyrosine-chlorambucil analogs were synthesized in order to generate new anticancer drugs with structural diversity, more specifically in regards to the phenol group location. These new analogs were produced in good yield following efficient synthetic methodology. All the tyrosine-chlorambucil hybrids were more effective than the parent drug, chlorambucil. In vitro biological evaluation on estrogen receptor positive and estrogen receptor negative (ER(+) and ER(-)) breast cancer cell lines revealed an enhanced cytotoxic activity for compounds with the phenol function located at position meta. Molecular docking calculations were performed for the pure L-ortho, L-meta- and L-para-tyrosine phenolic regioisomers. The synthesis of all tyrosine-chlorambucil hybrid regioisomers and their biological activity are reported herein. Possible orientations within the targeted protein [estrogen receptor alpha (ERα)] are discussed in relation to the biological activity.

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“…Previous studies show that nitrones can upregulate eNOS phosphorylation thereby reversing SIN-1-induced eNOS dysfunction, and have cytoprotective properties against SIN-1 induced peroxynitrite toxicity [16, 17]. Some nitrones can also induce endogenous antioxidant enzymes [18], inhibit NF-κB activation [19], as well as donate NO, thereby increasing NO bioavailability [20, 21].…”

Section: Introductionmentioning

confidence: 99%

Nitrones reverse hyperglycemia-induced endothelial dysfunction in bovine aortic endothelial cells

Headley

DiSilvestro

Bryant

et al. 2016

Biochemical Pharmacology

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Hyperglycemia has been implicated in the development of endothelial dysfunction through heightened ROS production. Since nitrones reverse eNOS dysfunction, increase antioxidant enzyme activity, and suppress pro-apoptotic signaling pathway and mitochondrial dysfunction from ROS-induced toxicity, the objective of this study was to determine whether nitrone spin traps DMPO, PBN and PBN-LA were effective at duplicating these effects and improving glucose uptake in an in vitro model of hyperglycemia-induced dysfunction using bovine aortic endothelial cells (BAEC). BAEC were cultured in DMEM medium with low (5.5 mM glucose, LG) or high glucose (50 mM, HG) for 14 days to model in vivo hyperglycemia as experienced in humans with metabolic disease. Improvements in cell viability, intracellular oxidative stress, NO and tetrahydrobiopterin levels, mitochondrial membrane potential, glucose transport, and activity of antioxidant enzymes were measured from single treatment of BAEC cells with nitrones for 24 h after hyperglycemia. Chronic hyperglycemia significantly increased intracellular ROS by 50%, decreased cell viability by 25%, reduced NO bioavailability by 50%, and decreased BH4 levels by 15% thereby decreasing NO production. Intracellular glucose transport and SOD activity were also decreased by 50% and 25% respectively. Nitrone (PBN and DMPO, 50 μM) treatment of BAEC cells grown in hyperglycemic conditions resulted in in the normalization of outcome measures except for SOD and catalase activities. Our findings demonstrate that the nitrones reverse the deleterious effects of hyperglycemia in BAEC cells. We believe that in vivo testing of these nitrone compounds in models of cardiometabolic disease is warranted.

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Spin Trapping and Cytoprotective Properties of Fluorinated Amphiphilic Carrier Conjugates of Cyclic versus Linear Nitrones

Cited by 22 publications

References 82 publications

Amphiphilic Amide Nitrones: A New Class of Protective Agents Acting as Modifiers of Mitochondrial Metabolism

Amphiphilic Amide Nitrones: A New Class of Protective Agents Acting as Modifiers of Mitochondrial Metabolism

SAR study of tyrosine–chlorambucil hybrid regioisomers; synthesis and biological evaluation against breast cancer cell lines

Nitrones reverse hyperglycemia-induced endothelial dysfunction in bovine aortic endothelial cells

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