The Experts below are selected from a list of 90 Experts worldwide ranked by ideXlab platform
James C. Fishbein - One of the best experts on this subject based on the ideXlab platform.
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interactions of the major metabolite of the cancer chemopreventive drug oltipraz with cytochrome c a novel pathway for cancer chemoprevention
Free Radical Biology and Medicine, 2007Co-Authors: Murugesan Velayutham, James C. Fishbein, Rajendra Bose Muthukumaran, Joe Z Sostaric, John Mccraken, Jay L. ZweierAbstract:Abstract The major metabolite of the cancer chemopreventive agent oltipraz, a Pyrrolopyrazine thione (PPD), has been shown to be a phase 2 enzyme inducer, an activity thought to be key to the cancer chemopreventive action of the parent compound. In cells, mitochondria are the major source of reactive oxygen species (ROS) and cytochrome c (cyt c ) is known to participate in mitochondrial electron transport and confer antioxidant and peroxidase activities. To understand possible mechanisms by which PPD acts as a phase 2 enzyme inducer, a study of its interaction with cyt c was undertaken. UV–visible spectroscopic results demonstrate that PPD is capable of reducing oxidized cyt c. The reduced cyt c is stable for a long period of time in the absence of an oxidizing agent. In the presence of ferricyanide, the reduced cyt c is rapidly oxidized back to its oxidized form. Further, UV–visible spectroscopic studies show that during the reduction process the coordination environment and redox state of iron in cyt c are changed. Low-temperature EPR studies show that during the reduction process, the heme iron changes from a low-spin state of s = 1/2 to a low-spin state of s = 0. Room-temperature EPR studies demonstrate that PPD inhibits the peroxidase activity of cyt c. EPR spin trapping experiments using DMPO show that PPD inhibits the superoxide radical scavenging activity of oxidized cyt c. From these results, we propose that PPD interacts with cyt c , binding to and then reducing the heme, and this may enhance ROS levels in mitochondria. This in turn could contribute to the mechanism by which the parent compound, oltipraz, might trigger the cancer chemopreventive increase in transcription of phase 2 enzymes. The modifications of cyt c function by the oltipraz metabolite may have implications for the regulation of apoptotic cell death.
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glutathione mediated formation of oxygen free radicals by the major metabolite of oltipraz
Chemical Research in Toxicology, 2005Co-Authors: Frederick A Villamena, Mettachit Navamal, James C. FishbeinAbstract:The major metabolite of the cancer chemopreventive oltipraz (1), a Pyrrolopyrazine thione, 4, has been shown to be a phase two enzyme inducer, an activity thought to be a key to the cancer chemopreventive action of the parent compound. To understand the possible mechanism by which the metabolite acts as an inducer, a study of its potential to generate free radicals was undertaken. Electron paramagnetic resonance (EPR) spin trapping studies using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) were performed with 7-methyl-6,8-bis-methyldisulfanyl-pyrrolo[1,2-a]pyrazine, 5, a synthetic precursor to the metabolite in aqueous and organic solvents. In the presence of GSH, which rapidly liberates the metabolite from the precursor, a 1:2:2:1 quartet spectrum with hyperfine coupling constants a(N) = a(H) = 14.9 G, characteristic of the hydroxyl radical adduct of DMPO, was observed in the presence of oxygen. No signal was seen under anaerobic conditions. This signal was quenched by the addition of the superoxide scavenging enzyme Cu,Zn-superoxide dismutase. In aqueous dimethyl sulfoxide (80 vol % DMSO), the metabolite precursor 5, GSH, and DMPO exhibited an EPR spectrum with the hyperfine values of a(N) = 12.7 G, a(H1) = 10.3 G, and a(H2) = 1.3 G, corresponding to the superoxide radical adduct of DMPO. The amount of superoxide radical adduct formed from the reaction of 5 and GSH increases with GSH concentration in phosphate buffer solution. Kinetic studies show that the formation of superoxide radical anion is first-order with respect to GSH. The formation of superoxide radical anion by the metabolite in the presence of GSH is linear at lower concentrations of 5 but becomes nonlinear at high concentrations. Overall, these studies suggest a mechanism in which GSH reduces the metabolite 4 to 4. , presumably a radical anion, that in turn donates an electron to oxygen resulting in superoxide radical anion formation. This GSH stimulated redox cycle of the metabolite 4 suggests a possible mechanism by which the parent compound oltipraz might effect the cancer chemopreventive increase in the transcription of phase two enzymes that is mediated by transcription factor Nrf2.
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Phase 2 Enzyme Induction by the Major Metabolite of Oltipraz
Chemical research in toxicology, 2003Co-Authors: Jacobus P. Petzer, Mi Kyoung Kwak, Thomas W. Kensler, Mettachit Navamal, Jesse K. Johnson, James C. FishbeinAbstract:Treatment for 48 h of murine Hepa 1c1c7 cells in culture with the cancer chemopreventive oltipraz (1) followed by addition of CD(3)I and immediate cell lysis yields, by LC/MS analysis, three isotopomers of the methylated Pyrrolopyrazine (2), a known human metabolite of oltipraz. The major isotopomer (58%) is the one containing two CD(3)- groups attached to the pendant sulfur atoms of the Pyrrolopyrazine ring, the others containing one CD(3)- and one CH(3)- group or two CH(3)- groups. It is concluded from this that the unmethylated Pyrrolopyrazine (4) is the major metabolite of oltipraz. Prodrugs 5 and 6, which have been shown to rapidly generate 4 in the presence of GSH at physiological pH, induce the phase 2 enzyme NQO1 in Hepa 1c1c7 cells with potencies on par with oltipraz itself: CD(NQO1) = 14.4 +/- 1.3, 20.1 +/- 4.6, and 23.6 +/- 1.6 microM for oltipraz, 5, and 6, respectively. Pretreatment of oltipraz, 5, and 6 in cell culture media with 1 mM GSH, which is shown to immediately convert 5 and 6 to 4, followed by incubation with Hepa 1c1c7 cells shows similar potencies for oltipraz and the (decomposed) produrgs, with CD(NQO1) = 18.0 +/- 4.4 microM for 5, 17.8 +/- 0.2 microM for 6, and 13.5 +/- 1.4 microM for oltipraz. Treatment with compound 6 of murine hepatoma cells containing a luciferase gene under the control of the antioxidant response element (ARE) from the mouse heme oxygenase (ho-1) gene elicits induction of luciferase activity, CD = 35.8 +/- 2.8 microM, somewhat greater than the potency than oltipraz itself. Western blots of nuclear proteins isolated from Hepa 1c1c7 cells and probed with anti-Nrf2 indicate that as compared to vehicle DMSO, compound 6 stimulates nuclear translocation of Nrf2 from the cytosol. From this study, it is concluded that the major metabolite of the cancer chemopreventive oltipraz is a phase 2 enzyme inducer of comparable potency that activates the ARE and initiates nuclear translocation of transcription factor Nrf 2.
Qingqing Zheng - One of the best experts on this subject based on the ideXlab platform.
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a transition metal free tandem process to pyrrolopyrazino 2 3 d pyridazine diones
ChemInform, 2012Co-Authors: Aiping Huang, Zhi Qiao, Xinhai Zhang, Qingqing ZhengAbstract:An effective and simple method for the synthesis of the title compounds (III) and (IV) is presented.
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a transition metal free tandem process to pyrrolopyrazino 2 3 d pyridazine diones
Tetrahedron, 2012Co-Authors: Aiping Huang, Zhi Qiao, Xinhai Zhang, Qingqing ZhengAbstract:Abstract A transition metal-free tandem process for the synthesis of pyrrolopyrazino[2,3-d]pyridazine-diones is described. The process is an efficient construction of this tricyclic system by a one-pot coupling/Smiles rearrangement/cyclization approach. This methodology has potential applications in the synthesis of biologically and medicinally relevant compounds.
Jonathan R Scheerer - One of the best experts on this subject based on the ideXlab platform.
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synthesis of peramine an anti insect defensive alkaloid produced by endophytic fungi of cool season grasses
Journal of Natural Products, 2016Co-Authors: Matthew R Olfe Nelli, Jonathan R ScheererAbstract:A seven-step synthesis of peramine, which required three chromatographic separations, is described. Key to the synthesis is an enolate alkylation of a pyrrole-fused diketopiperazine, reduction of the acyl pyrrole, and dehydration of the intermediate pyrrolyl carbinol to establish the Pyrrolopyrazine core of peramine.
Aiping Huang - One of the best experts on this subject based on the ideXlab platform.
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a transition metal free tandem process to pyrrolopyrazino 2 3 d pyridazine diones
ChemInform, 2012Co-Authors: Aiping Huang, Zhi Qiao, Xinhai Zhang, Qingqing ZhengAbstract:An effective and simple method for the synthesis of the title compounds (III) and (IV) is presented.
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a transition metal free tandem process to pyrrolopyrazino 2 3 d pyridazine diones
Tetrahedron, 2012Co-Authors: Aiping Huang, Zhi Qiao, Xinhai Zhang, Qingqing ZhengAbstract:Abstract A transition metal-free tandem process for the synthesis of pyrrolopyrazino[2,3-d]pyridazine-diones is described. The process is an efficient construction of this tricyclic system by a one-pot coupling/Smiles rearrangement/cyclization approach. This methodology has potential applications in the synthesis of biologically and medicinally relevant compounds.
Jay L. Zweier - One of the best experts on this subject based on the ideXlab platform.
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interactions of the major metabolite of the cancer chemopreventive drug oltipraz with cytochrome c a novel pathway for cancer chemoprevention
Free Radical Biology and Medicine, 2007Co-Authors: Murugesan Velayutham, James C. Fishbein, Rajendra Bose Muthukumaran, Joe Z Sostaric, John Mccraken, Jay L. ZweierAbstract:Abstract The major metabolite of the cancer chemopreventive agent oltipraz, a Pyrrolopyrazine thione (PPD), has been shown to be a phase 2 enzyme inducer, an activity thought to be key to the cancer chemopreventive action of the parent compound. In cells, mitochondria are the major source of reactive oxygen species (ROS) and cytochrome c (cyt c ) is known to participate in mitochondrial electron transport and confer antioxidant and peroxidase activities. To understand possible mechanisms by which PPD acts as a phase 2 enzyme inducer, a study of its interaction with cyt c was undertaken. UV–visible spectroscopic results demonstrate that PPD is capable of reducing oxidized cyt c. The reduced cyt c is stable for a long period of time in the absence of an oxidizing agent. In the presence of ferricyanide, the reduced cyt c is rapidly oxidized back to its oxidized form. Further, UV–visible spectroscopic studies show that during the reduction process the coordination environment and redox state of iron in cyt c are changed. Low-temperature EPR studies show that during the reduction process, the heme iron changes from a low-spin state of s = 1/2 to a low-spin state of s = 0. Room-temperature EPR studies demonstrate that PPD inhibits the peroxidase activity of cyt c. EPR spin trapping experiments using DMPO show that PPD inhibits the superoxide radical scavenging activity of oxidized cyt c. From these results, we propose that PPD interacts with cyt c , binding to and then reducing the heme, and this may enhance ROS levels in mitochondria. This in turn could contribute to the mechanism by which the parent compound, oltipraz, might trigger the cancer chemopreventive increase in transcription of phase 2 enzymes. The modifications of cyt c function by the oltipraz metabolite may have implications for the regulation of apoptotic cell death.
