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Antihypertensive effect of mitochondria-targeted proxyl nitroxides.
Dikalova AE, Kirilyuk IA, Dikalov SI
(2015) Redox Biol 4: 355-62
MeSH Terms: Angiotensin II, Animals, Antihypertensive Agents, Antioxidants, Aorta, Blood Pressure, Cell Line, Cyclic N-Oxides, Endothelial Cells, Humans, Hydrogen Peroxide, Hypertension, Infusion Pumps, Implantable, Male, Mice, Mice, Inbred C57BL, Mitochondria, Molecular Targeted Therapy, Organophosphorus Compounds, Piperidines, Superoxides
Show Abstract · Added February 17, 2016
Superoxide ( [Formula: see text] ) has been implicated in the pathogenesis of many human diseases including hypertension. Mitochondria-targeted superoxide scavenger mitoTEMPO reduces blood pressure; however, the structure-functional relationships in antihypertensive effect of mitochondria-targeted nitroxides remain unclear. The nitroxides are known to undergo bioreduction into hydroxylamine derivatives which reacts with [Formula: see text] with much lower rate. The nitroxides of pyrrolidine series (proxyls) are much more resistant to bioreduction compared to TEMPOL derivatives suggesting that mitochondria-targeted proxyls can be effective antioxidants with antihypertensive activity. In this work we have designed and studied two new pyrrolidine mitochondria targeted nitroxides: 3-[2-(triphenyphosphonio)acetamido]- and 3-[2-(triphenyphosphonio) acetamidomethyl]-2,2,5,5-tetramethylpyrrolidine-1-oxyl (mCP2) and (mCP1). These new mitochondria targeted nitroxides have 3- to 7-fold lower rate constants of the reaction with O2(-•) compared with mitoTEMPO; however, the cellular bioreduction of mCP1 and mCP2 was 3- and 2-fold slower. As a consequence incubation with cells afforded much higher intracellular concentration of mCP1 and mCP2 nitroxides compared to mitoTEMPO nitroxide. This has compensated for the difference in the rate of O2(-•) scavenging and all nitroxides similarly protected mitochondrial respiration in H2O2 treated endothelial cells. Treatment of hypertensive mice with mCP1 and mCP2 (1.4mg/kg/day) after onset of angiotensin II-induced hypertension significantly reduced blood pressure to 133±5mmHg and 129±6mmHg compared to 163±5mmHg in mice infused with angiotensin II alone. mCP1 and mCP2 reduced vascular O2(-•) and prevented decrease of endothelial nitric oxide production. These data indicate that resistance to bioreduction play significant role in antioxidant activity of nitroxides. Studies of nitroxide analogs such as mCP1 and mCP2 may help in optimization of chemical structure of mitochondria-targeted nitroxides for improved efficacy and pharmacokinetics of these drugs in treatment of hypertension and many other conditions including atherosclerosis, diabetes and degenerative neurological disorders in which mitochondrial oxidative stress seems to play a role.
Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
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21 MeSH Terms
Ion/ion reactions with "onium" reagents: an approach for the gas-phase transfer of organic cations to multiply-charged anions.
Gilbert JD, Prentice BM, McLuckey SA
(2015) J Am Soc Mass Spectrom 26: 818-25
MeSH Terms: Alkylation, CME-Carbodiimide, Catalysis, Chelating Agents, Cross-Linking Reagents, Edetic Acid, Energy Transfer, Hot Temperature, Indicators and Reagents, Models, Molecular, Oligopeptides, Organophosphorus Compounds, Protein Conformation, Quaternary Ammonium Compounds, Spectrometry, Mass, Electrospray Ionization, Static Electricity, Sulfonium Compounds, Tandem Mass Spectrometry, Tetraethylammonium, Volatilization
Show Abstract · Added August 17, 2016
The use of ion/ion reactions to effect gas-phase alkylation is demonstrated. Commonly used fixed-charge "onium" cations are well-suited for ion/ion reactions with multiply deprotonated analytes because of their tendency to form long-lived electrostatic complexes. Activation of these complexes results in an SN2 reaction that yields an alkylated anion with the loss of a neutral remnant of the reagent. This alkylation process forms the basis of a general method for alkylation of deprotonated analytes generated via electrospray, and is demonstrated on a variety of anionic sites. SN2 reactions of this nature are demonstrated empirically and characterized using density functional theory (DFT). This method for modification in the gas phase is extended to the transfer of larger and more complex R groups that can be used in later gas-phase synthesis steps. For example, N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide (CMC) is used to transfer a carbodiimide functionality to a peptide anion containing a carboxylic acid. Subsequent activation yields a selective reaction between the transferred carbodiimide group and a carboxylic acid, suggesting the carbodiimide functionality is retained through the transfer process. Many different R groups are transferable using this method, allowing for new possibilities for charge manipulation and derivatization in the gas phase.
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20 MeSH Terms
Synthesis and characterization of oligonucleotides containing a nitrogen mustard formamidopyrimidine monoadduct of deoxyguanosine.
Christov PP, Son KJ, Rizzo CJ
(2014) Chem Res Toxicol 27: 1610-8
MeSH Terms: Base Sequence, DNA Adducts, DNA Repair, DNA-Formamidopyrimidine Glycosylase, Deoxyguanosine, Deoxyribonuclease IV (Phage T4-Induced), Electrophoresis, Agar Gel, Escherichia coli, Escherichia coli Proteins, Kinetics, Mechlorethamine, Oligonucleotides, Organophosphorus Compounds, Pyrimidines
Show Abstract · Added January 7, 2016
N(5)-Substituted formamidopyrimidine adducts have been observed from the reaction of dGuo or DNA with aziridine containing electrophiles, including nitrogen mustards. However, the role of substituted Fapy-dGuo adducts in the biological response to nitrogen mustards and related species has not been extensively explored. We have developed chemistry for the site-specific synthesis of oligonucleotides containing an N(5)-nitrogen mustard Fapy-dGuo using the phosphoramidite approach. The lesion was found to be a good substrate for Escherichia coli endonuclease IV and formamidopyrimidine glycosylase.
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14 MeSH Terms
Does scavenging of mitochondrial superoxide attenuate cancer prosurvival signaling pathways?
Nazarewicz RR, Dikalova A, Bikineyeva A, Ivanov S, Kirilyuk IA, Grigor'ev IA, Dikalov SI
(2013) Antioxid Redox Signal 19: 344-9
MeSH Terms: Animals, Apoptosis, Cell Line, Tumor, Cell Survival, Humans, Mice, Mitochondria, Neoplasms, Organophosphorus Compounds, Piperidines, Signal Transduction, Superoxides
Show Abstract · Added March 30, 2014
It has been previously suggested that overexpression of mitochondrial superoxide dismutase (SOD) attenuates cancer development; however, the exact mechanism remains unclear. In this work, we have studied the direct effect of the mitochondria-targeted superoxide scavenger, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), on B16-F0 mouse melanoma cells and tumor growth in a nude mouse model of human melanoma. We show that scavenging of mitochondrial superoxide inhibited cell growth, reduced viability, and induced apoptosis in melanoma cells, but did not affect nonmalignant skin fibroblasts. Diminished mitochondrial superoxide inhibited redox-dependent Akt, restored activity of mitochondrial pyruvate dehydrogenase, and reduced HIF1-α and lactate dehydrogenase expression in cancer cells. Suppression of glycolysis in mitoTEMPO-treated melanoma cells resulted in a significant drop of cellular adenosine-5'-triphosphate and induced cell death. In vivo mitoTEMPO treatment effectively suppressed growth of established tumor in the mouse model of human melanoma. Therefore, our data lead to the hypothesis that scavenging of mitochondrial superoxide selectively inhibits redox-sensitive survival and metabolic pathways, resulting in cancer cell death. In contrast to existing anticancer therapies, inhibition of mitochondrial superoxide may represent a novel specific anticancer treatment with reduced cytotoxic side effects.
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12 MeSH Terms
Cross talk between mitochondria and NADPH oxidases.
Dikalov S
(2011) Free Radic Biol Med 51: 1289-301
MeSH Terms: Aging, Angiotensin II, Animals, Antioxidants, Atherosclerosis, Diabetes Mellitus, Humans, Hypertension, Mice, Mitochondria, NADPH Oxidases, Neurodegenerative Diseases, Nitric Oxide Synthase Type III, Organophosphorus Compounds, Oxidation-Reduction, Oxidative Stress, Piperidines, Rabbits, Rats, Reactive Oxygen Species, Signal Transduction, Superoxide Dismutase, Xanthine Oxidase
Show Abstract · Added February 17, 2016
Reactive oxygen species (ROS) play an important role in physiological and pathological processes. In recent years, a feed-forward regulation of the ROS sources has been reported. The interactions between the main cellular sources of ROS, such as mitochondria and NADPH oxidases, however, remain obscure. This work summarizes the latest findings on the role of cross talk between mitochondria and NADPH oxidases in pathophysiological processes. Mitochondria have the highest levels of antioxidants in the cell and play an important role in the maintenance of cellular redox status, thereby acting as an ROS and redox sink and limiting NADPH oxidase activity. Mitochondria, however, are not only a target for ROS produced by NADPH oxidase but also a significant source of ROS, which under certain conditions may stimulate NADPH oxidases. This cross talk between mitochondria and NADPH oxidases, therefore, may represent a feed-forward vicious cycle of ROS production, which can be pharmacologically targeted under conditions of oxidative stress. It has been demonstrated that mitochondria-targeted antioxidants break this vicious cycle, inhibiting ROS production by mitochondria and reducing NADPH oxidase activity. This may provide a novel strategy for treatment of many pathological conditions including aging, atherosclerosis, diabetes, hypertension, and degenerative neurological disorders in which mitochondrial oxidative stress seems to play a role. It is conceivable that the use of mitochondria-targeted treatments would be effective in these conditions.
Copyright © 2011 Elsevier Inc. All rights reserved.
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23 MeSH Terms
Semisynthesis of 6-chloropurine-2'-deoxyriboside 5'-dimethoxytrityl 3'-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite and its use in the synthesis of fluorescently labeled oligonucleotides.
Uddin MJ, Schulte MI, Maddukuri L, Harp J, Marnett LJ
(2010) Nucleosides Nucleotides Nucleic Acids 29: 831-40
MeSH Terms: Cadaverine, Chromatography, Gel, Chromatography, High Pressure Liquid, Crystallography, Fluorescent Dyes, Magnetic Resonance Spectroscopy, Mass Spectrometry, Molecular Structure, Nucleic Acid Conformation, Oligonucleotides, Organophosphorus Compounds, Pentosyltransferases, Purine Nucleosides, Purines, Rhodamines, Spectrometry, Fluorescence
Show Abstract · Added March 7, 2014
An efficient enzymatic synthesis of 6-chloropurine-2'-deoxyriboside from the reaction of 6-chloropurine with 2'-deoxycytidine catalyzed by nucleoside-2'-deoxyribosyltransferase (E.C. 2.4.2.6) followed by chemical conversion into the 5'-dimethoxytrityl 3'-(2-cyanoethyl-N,N-diisopropylamino) phosphoramidite derivative is described. The phosphoramidite derivative was incorporated site-specifically into an oligonucleotide and used for the introduction of a tethered tetramethylrhodamine-cadaverine conjugate. The availability of an efficient route to 6-chloropurine-2'-deoxyriboside 5'-dimethoxytrityl 3'-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite enables the facile synthesis of oligonucleotides containing a range of functional groups tethered to deoxyadenosine residues.
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16 MeSH Terms
Ex vivo oxidation in tissue and plasma assays of hydroxyoctadecadienoates: Z,E/E,E stereoisomer ratios.
Liu W, Yin H, Akazawa YO, Yoshida Y, Niki E, Porter NA
(2010) Chem Res Toxicol 23: 986-95
MeSH Terms: Animals, Borohydrides, Chromatography, High Pressure Liquid, Female, Gas Chromatography-Mass Spectrometry, Linoleic Acids, Linoleic Acids, Conjugated, Mice, Mice, Inbred BALB C, Organophosphorus Compounds, Oxidation-Reduction, Stereoisomerism, Tandem Mass Spectrometry
Show Abstract · Added March 7, 2014
The primary products from peroxidation of linoleate in biological tissues and fluids are the hydroperoxy octadecadienoates, and the products normally assayed, after reduction of the hydroperoxides, are the corresponding hydroxy octadecadienoates (HODEs). The HODEs are found in tissues and fluids as a mixture of Z,E and E,E stereoisomers. Two regioisomeric sets of Z,E and E,E stereoisomers are normally observed with substitution at the 9- and 13-positions of the 18-carbon chain. The Z,E/E,E product ratio has proved to be a useful means for assessing the reducing capacity of the medium undergoing peroxidation. The HODE Z,E/E,E product ratios previously reported for tissues such as liver and brain vary from 0.5 to 2.0, and plasma ratios are somewhat higher, between 2.0 and 3.0. The reported literature protocols for HODE assay in tissues involve homogenization, reduction with sodium borohydride in the presence of BHT, and ester hydrolysis with KOH to give the free HODEs. This is followed by either reverse-phase HPLC of the free acid HODEs or by conversion to TMS derivatives and GC-MS. When sodium borohydride is replaced in the protocol by triphenylphosphine, a gentler reducing agent, HODE Z,E/E,E product ratios are much higher, and lower total HODE levels of are found. It is proposed that inclusion of sodium borohydride in the isolation procedures leads to ex vivo reactions that are avoided if triphenylphosphine is used as the reducing agent. Modified protocols for HODE analyses (tissue and plasma methods #2) are described that should be used for assays of tissues and fluids.
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13 MeSH Terms
Site-specific synthesis and characterization of oligonucleotides containing an N6-(2-deoxy-D-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-N-methylformamidopyrimidine lesion, the ring-opened product from N7-methylation of deoxyguanosine.
Christov PP, Brown KL, Kozekov ID, Stone MP, Harris TM, Rizzo CJ
(2008) Chem Res Toxicol 21: 2324-33
MeSH Terms: Chromatography, High Pressure Liquid, DNA Damage, Deoxyguanosine, Formamides, Magnetic Resonance Spectroscopy, Methylation, Oligonucleotides, Organophosphorus Compounds, Pyrimidines, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added May 29, 2014
A phosphoramidite reagent of N6-(2-deoxy-D-erythro-pentofuranosyl)-2,6-diamino-1,4-dihydro-4-oxo-5-N-methylformamidopyrimidine (MeFapy-dGuo) lesions was synthesized in four steps from 2'-deoxyguanosine. Fapy nucleosides can rearrange to the pyranose form when the 5'-hydroxyl group is unprotected. The phosphoramidite was incorporated into oligonucleotides using solid-phase synthesis by adjusting the deprotection time for removal of the 5'-dimethoxytrityl group of the MeFapy-dGuo nucleotide, thereby minimizing its rearrangement to the ribopyranose. The furanose and pyranose forms were differentiated by a series of two-dimensional NMR experiments.
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10 MeSH Terms
Using 3'-bridging phosphorothiolates to isolate the forward DNA cleavage reaction of human topoisomerase IIalpha.
Deweese JE, Burgin AB, Osheroff N
(2008) Biochemistry 47: 4129-40
MeSH Terms: Antigens, Neoplasm, Base Sequence, DNA, DNA Primers, DNA Topoisomerases, Type II, DNA-Binding Proteins, Humans, Hydrolysis, Kinetics, Organophosphorus Compounds, Sulfhydryl Compounds
Show Abstract · Added March 5, 2014
The ability to cleave DNA is critical to the cellular and pharmacological functions of human type II topoisomerases. However, the low level of cleavage at equilibrium and the tight coupling of the cleavage and ligation reactions make it difficult to characterize the mechanism by which these enzymes cut DNA. Therefore, to establish a system that isolates topoisomerase II-mediated DNA scission from ligation, oligonucleotide substrates were developed that contained a 3'-bridging phosphorothiolate at the scissile bond. Scission of these substrates generates a 3'-terminal -SH moiety that is a poor nucleophile relative to the normal 3'-terminal -OH group. Consequently, topoisomerase II cannot efficiently ligate phosphorothiolate substrates once they are cleaved. The characteristics of topoisomerase IIalpha-mediated cleavage of phosphorothiolate oligonucleotides were identical to those seen with wild-type substrates, except that no ligation was observed. This unidirectional accumulation of cleavage complexes provided critical information regarding coordination of the protomer subunits of topoisomerase IIalpha and the mechanism of action of topoisomerase II poisons. Results indicate that the two enzyme subunits are partially coordinated and that cleavage at one scissile bond increases the degree of cleavage at the other. Furthermore, anticancer drugs such as etoposide and amsacrine that strongly inhibit topoisomerase II-mediated DNA ligation have little effect on the forward scission reaction. In contrast, abasic sites that increase levels of cleavage complexes without affecting ligation stimulate the forward rate of scission. Phosphorothiolate substrates provide significant advantages over traditional "suicide substrates" and should be valuable for future studies on DNA scission and the topoisomerase II-DNA cleavage complex.
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11 MeSH Terms
Synthesis of oligonucleotides containing the N2-deoxyguanosine adduct of the dietary carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline.
Stover JS, Rizzo CJ
(2007) Chem Res Toxicol 20: 1972-9
MeSH Terms: Carcinogens, Circular Dichroism, Deoxyguanosine, Electrophoresis, Capillary, Oligonucleotides, Organophosphorus Compounds, Quinolines
Show Abstract · Added January 7, 2016
2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a highly mutagenic heterocyclic amine formed in all cooked meats. IQ has been found to be a potent inducer of frameshift mutations in bacteria and carcinogenic in laboratory animals. Upon metabolic activation, IQ forms covalent adducts at the C8- and N2-positions of deoxyguanosine with a relative ratio of up to approximately 4:1. We have previously incorporated the major dGuo-C8-IQ adduct into oligonucleotides through the corresponding phosphoramidite reagent. We report here the sequence-specific synthesis of oligonucleotides containing the minor dGuo-N2-IQ adduct. Thermal melting analysis revealed that the dGuo-N2-IQ adduct significantly destabilizes duplex DNA.
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7 MeSH Terms