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David H Sherman - One of the best experts on this subject based on the ideXlab platform.
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oxad a versatile indolic Nitrone synthase from the marine derived fungus penicillium oxalicum f30
Journal of the American Chemical Society, 2016Co-Authors: Sean A Newmister, Madeleine M. Joullie, Claire M Gober, Stelamar Romminger, Ashootosh Tripathi, Lizbeth L L Parra, Robert M Williams, Roberto G S Berlinck, David H ShermanAbstract:Indole alkaloids are a diverse class of natural products known for their wide range of biological activities and complex chemical structures. Rarely observed in this class are indolic Nitrones, such as avrainvillamide and waikialoid, which possess potent bioactivities. Herein the oxa gene cluster from the marine-derived fungus Penicillium oxalicum F30 is described along with the characterization of OxaD, a flavin-dependent oxidase that generates roquefortine L, a Nitrone-bearing intermediate in the biosynthesis of oxaline. Nitrone functionality in roquefortine L was confirmed by spectroscopic methods and 1,3-dipolar cycloaddition with methyl acrylate. OxaD is a versatile biocatalyst that converts an array of semisynthetic roquefortine C derivatives bearing indoline systems to their respective Nitrones. This work describes the first implementation of a Nitrone synthase as a biocatalyst and establishes a novel platform for late-stage diversification of a range of complex natural products.
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OxaD: A Versatile Indolic Nitrone Synthase from the Marine-Derived Fungus Penicillium oxalicum F30
2016Co-Authors: Sean A Newmister, Stelamar Romminger, Ashootosh Tripathi, Lizbeth L L Parra, Robert M Williams, Roberto G S Berlinck, Claire M. Gober, Madeleine M. Joullié, David H ShermanAbstract:Indole alkaloids are a diverse class of natural products known for their wide range of biological activities and complex chemical structures. Rarely observed in this class are indolic Nitrones, such as avrainvillamide and waikialoid, which possess potent bioactivities. Herein the oxa gene cluster from the marine-derived fungus Penicillium oxalicum F30 is described along with the characterization of OxaD, a flavin-dependent oxidase that generates roquefortine L, a Nitrone-bearing intermediate in the biosynthesis of oxaline. Nitrone functionality in roquefortine L was confirmed by spectroscopic methods and 1,3-dipolar cycloaddition with methyl acrylate. OxaD is a versatile biocatalyst that converts an array of semisynthetic roquefortine C derivatives bearing indoline systems to their respective Nitrones. This work describes the first implementation of a Nitrone synthase as a biocatalyst and establishes a novel platform for late-stage diversification of a range of complex natural products
Frederick A Villamena - One of the best experts on this subject based on the ideXlab platform.
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substituted α phenyl and α naphthlyl n tert butyl Nitrones synthesis spin trapping and neuroprotection evaluation
Journal of Organic Chemistry, 2020Co-Authors: Anais Deletraz, Frederick A Villamena, B N Tuccio, Kamal Zeamari, Kangyu Hua, Maud Combes, Noelle Callizot, Gregory DurandAbstract:New derivatives of α-phenyl-N-tert-butyl Nitrone (PBN) bearing a hydroxyl, an acetate, or an acetamide substituent on the N-tert-butyl moiety and para-substituted phenyl or naphthlyl moieties were synthesized. Their ability to trap hydroxymethyl radical was evaluated by electron paramagnetic resonance spectroscopy. The presence of two electron-withdrawing substituents on both sides of the nitronyl function improves the spin-trapping properties, with 4-HOOC-PBN-CH2OAc and 4-HOOC-PBN-CH2NHAc being ∼4× more reactive than PBN. The electrochemical properties of the derivatives were further investigated by cyclic voltammetry and showed that the redox potentials of the Nitrones are largely influenced by the nature of the substituents both on the aromatic ring and on the N-tert-butyl function. The acetamide derivatives PBN-CH2NHAc, 4-AcNHCH2-PBN-CH2NHAc, and 4-MeO-PBN-CH2NHAc were the easiest to oxidize. A computational approach was used to rationalize the effect of functionalization on the free energies of Nitrone reactivity with hydroxymethyl radical as well as on the electron affinity and ionization potential. Finally, the neuroprotection of the derivatives was evaluated in an in vitro model of cellular injury on cortical neurons. Five derivatives showed good protection at very low concentrations (0.1-10 μM), with PBN-CH2NHAc and 4-HOOC-PBN being the two most promising agents.
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inhibition of ros induced apoptosis in endothelial cells by Nitrone spin traps via induction of phase ii enzymes and suppression of mitochondria dependent pro apoptotic signaling
Biochemical Pharmacology, 2012Co-Authors: Amlan Das, Bhavani Gopalakrishnan, Oliver H Voss, Andrea I Doseff, Frederick A VillamenaAbstract:Oxidative stress is the main etiological factor behind the pathogenesis of various diseases including inflammation, cancer, cardiovascular and neurodegenerative disorders. Due to the spin trapping abilities and various pharmacological properties of Nitrones, their application as therapeutic agent has been gaining attention. Though the antioxidant properties of the Nitrones are well known, the mechanism by which they modulate the cellular defense machinery against oxidative stress is not well investigated and requires further elucidation. Here, we have investigated the mechanisms of cytoprotection of the Nitrone spin traps against oxidative stress in bovine aortic endothelial cells (BAEC). Cytoprotective properties of both the cyclic Nitrone 5,5-dimethyl-pyrroline N-oxide (DMPO) and linear Nitrone α-phenyl N-tert-butyl Nitrone (PBN) against H₂O₂-induced cytotoxicity were investigated. Preincubation of BAEC with PBN or DMPO resulted in the inhibition of H₂O₂-mediated cytotoxicity and apoptosis. Nitrone-treatment resulted in the induction and restoration of phase II antioxidant enzymes via nuclear translocation of NF-E2-related factor 2 (Nrf-2) in oxidatively-challenged cells. Furthermore, the Nitrones were found to inhibit the mitochondrial depolarization and subsequent activation of caspase-3 induced by H₂O₂. Significant down-regulation of the pro-apoptotic proteins p53 and Bax, and up-regulation of the anti-apoptotic proteins Bcl-2 and p-Bad were observed when the cells were preincubated with the Nitrones prior to H₂O₂-treatment. It was also observed that Nrf-2 silencing completely abolished the protective effects of Nitrones. Hence, these findings suggest that Nitrones confer protection to the endothelial cells against oxidative stress by modulating phase II antioxidant enzymes and subsequently inhibiting mitochondria-dependent apoptotic cascade.
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potential implication of the chemical properties and bioactivity of Nitrone spin traps for therapeutics
Future Medicinal Chemistry, 2012Co-Authors: Frederick A Villamena, Amlan Das, Kevin M NashAbstract:Nitrone therapeutics has been employed in the treatment of oxidative stress-related diseases such as neurodegeneration, cardiovascular disease and cancer. The Nitrone-based compound NXY-059, which is the first drug to reach clinical trials for the treatment of acute ischemic stroke, has provided promise for the development of more robust pharmacological agents. However, the specific mechanism of Nitrone bioactivity remains unclear. In this review, we present a variety of Nitrone chemistry and biological activity that could be implicated for the Nitrone’s pharmacological activity. The chemistries of spin trapping and spin adduct reveal insights on the possible roles of Nitrones for altering cellular redox status through radical scavenging or nitric oxide donation, and their biological effects are presented. An interdisciplinary approach towards the development of novel synthetic antioxidants with improved pharmacological properties encompassing theoretical, synthetic, biochemical and in vitro/in vivo studies is covered.
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reactivities of superoxide and hydroperoxyl radicals with disubstituted cyclic Nitrones a dft study
Journal of Physical Chemistry A, 2012Co-Authors: Shangu Kim, Frederick A VillamenaAbstract:The unique ability of Nitrone spin traps to detect and characterize transient free radicals by electron paramagnetic resonance (EPR) spectroscopy has fueled the development of new spin traps with improved properties. Among a variety of free radicals in chemical and biological systems, superoxide radical anion (O2•–) plays a critical role as a precursor to other more oxidizing species such as hydroxyl radical (HO•), peroxynitrite (ONOO–), and hypochlorous acid (HOCl), and therefore the direct detection of O2•– is important. To overcome the limitations of conventional cyclic Nitrones, that is, poor reactivity with O2•–, instability of the O2•– adduct, and poor cellular target specificity, synthesis of disubstituted Nitrones has become attractive. Disubstituted Nitrones offer advantages over the monosubstituted ones because they allow bifunctionalization of spin traps, therefore accommodating all the desired spin trap properties in one molecular design. However, because of the high number of possible disubst...
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reactivity of superoxide radical anion and hydroperoxyl radical with α phenyl n tert butylNitrone pbn derivatives
Journal of Physical Chemistry A, 2008Co-Authors: Gregory Durand, Fanny Choteau, Bernard Pucci, Frederick A VillamenaAbstract:Nitrones have exhibited pharmacological activity against radical-mediated pathophysiological conditions and as analytical reagents for the identification of transient radical species by electron paramagnetic resonance (EPR) spectroscopy. In this work, competitive spin trapping, stopped-flow kinetics, and density functional theory (DFT) were employed to assess and predict the reactivity of O2•− and HO2• with various para-substituted α-phenyl-N-tert-butylNitrone (PBN) spin traps. Rate constants of O2•− trapping by Nitrones were determined using competitive UV−vis stopped-flow method with phenol red (PR) as probe, while HO2• trapping rate constants were calculated using competition kinetics with 5,5-dimethylpyrroline N-oxide (DMPO) by employing EPR spectroscopy. The effects of the para substitution on the charge density of the nitronyl-carbon and on the free energies of Nitrone reactivity with O2•− and HO2• were computationally rationalized at the PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) level of theory. Theore...
Cosimo Altomare - One of the best experts on this subject based on the ideXlab platform.
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inhibition of 6 hydroxydopamine induced oxidative damage by 4 5 dihydro 3h 2 benzazepine n oxides
Biochemical Pharmacology, 2008Co-Authors: Ramon Sotootero, Estefania Mendezalvarez, Sofia Sancheziglesias, Fedor I Zubkov, Leonid G Voskressensky, A V Varlamov, Modesto De Candia, Cosimo AltomareAbstract:Abstract A number of new analogs of 3,3-dimethyl-4,5-dihydro-3 H -2-benzazepine 2-oxide, structurally related to the Nitrone spin trap α-phenyl- N - tert -butylNitrone (PBN), were synthesized and evaluated for their activity in vitro as protectants against oxidative stress induced in rat brain mitochondria by 6-hydroxydopamine (6-OHDA), a neurotoxin producing experimental model of Parkinson's disease (PD). As assessed by a fluorimetric assay, all 2-benzazepine-based Nitrones were shown to decrease hydroxyl radicals ( OH) generated during 6-OHDA autoxidation. The inhibition effects on the OH formation shown by the 5- gem -dimethyl derivatives, 2–4 times higher than those of the corresponding 5-methyl derivatives, were attributed to the flattening effect of the 5- gem -dimethyl group on the azepine ring, which should enhance Nitrone reactivity and/or increase stability of the radical adducts. In contrast, owing to steric hindrance, a methyl group to C-1 diminishes the OH-scavenging activity of the Nitrone group. All the assayed compounds were more potent than PBN as inhibitors of 6-OHDA-induced lipid peroxidation (LPO) and protein carbonylation (PCO), taken as an indicator of mitochondrial protein oxidative damage. The most promising antioxidant (compound 11 ), bearing 5- gem -dimethyl and spiro C-3 cyclohexyl groups, highlighted in this study as the best features, inhibited LPO and PCO with IC 50 values of 20 and 48 μM, respectively, showing a potency improvement over PBN of two order magnitude. Both LPO and PCO inhibition potency data were found primarily related to the OH-scavenging activities, whereas lipophilicity plays a role in improving the LPO (but not PCO) inhibition, as a statistically valuable two-parameter equation proved.
Sean A Newmister - One of the best experts on this subject based on the ideXlab platform.
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oxad a versatile indolic Nitrone synthase from the marine derived fungus penicillium oxalicum f30
Journal of the American Chemical Society, 2016Co-Authors: Sean A Newmister, Madeleine M. Joullie, Claire M Gober, Stelamar Romminger, Ashootosh Tripathi, Lizbeth L L Parra, Robert M Williams, Roberto G S Berlinck, David H ShermanAbstract:Indole alkaloids are a diverse class of natural products known for their wide range of biological activities and complex chemical structures. Rarely observed in this class are indolic Nitrones, such as avrainvillamide and waikialoid, which possess potent bioactivities. Herein the oxa gene cluster from the marine-derived fungus Penicillium oxalicum F30 is described along with the characterization of OxaD, a flavin-dependent oxidase that generates roquefortine L, a Nitrone-bearing intermediate in the biosynthesis of oxaline. Nitrone functionality in roquefortine L was confirmed by spectroscopic methods and 1,3-dipolar cycloaddition with methyl acrylate. OxaD is a versatile biocatalyst that converts an array of semisynthetic roquefortine C derivatives bearing indoline systems to their respective Nitrones. This work describes the first implementation of a Nitrone synthase as a biocatalyst and establishes a novel platform for late-stage diversification of a range of complex natural products.
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OxaD: A Versatile Indolic Nitrone Synthase from the Marine-Derived Fungus Penicillium oxalicum F30
2016Co-Authors: Sean A Newmister, Stelamar Romminger, Ashootosh Tripathi, Lizbeth L L Parra, Robert M Williams, Roberto G S Berlinck, Claire M. Gober, Madeleine M. Joullié, David H ShermanAbstract:Indole alkaloids are a diverse class of natural products known for their wide range of biological activities and complex chemical structures. Rarely observed in this class are indolic Nitrones, such as avrainvillamide and waikialoid, which possess potent bioactivities. Herein the oxa gene cluster from the marine-derived fungus Penicillium oxalicum F30 is described along with the characterization of OxaD, a flavin-dependent oxidase that generates roquefortine L, a Nitrone-bearing intermediate in the biosynthesis of oxaline. Nitrone functionality in roquefortine L was confirmed by spectroscopic methods and 1,3-dipolar cycloaddition with methyl acrylate. OxaD is a versatile biocatalyst that converts an array of semisynthetic roquefortine C derivatives bearing indoline systems to their respective Nitrones. This work describes the first implementation of a Nitrone synthase as a biocatalyst and establishes a novel platform for late-stage diversification of a range of complex natural products
Keiji Maruoka - One of the best experts on this subject based on the ideXlab platform.
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asymmetric 1 3 dipolar cycloadditions of Nitrones and methacrolein catalyzed by chiral bis titanium lewis acid a dramatic effect of n substituent on Nitrone
Organic Letters, 2007Co-Authors: Takuya Hashimoto, Masato Omote, Taichi Kano, Keiji MaruokaAbstract:Highly stereoselective 1,3-dipolar cycloadditions of methacrolein and Nitrones could be realized by the use of bis-titanium chiral Lewis acid catalyst. Key to the success is the introduction of bulky N-substituent on Nitrone to attenuate the undesired Lewis acid−Nitrone complexation.
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asymmetric 1 3 dipolar cycloaddition reaction of Nitrones and acrolein with a bis titanium catalyst as chiral lewis acid
ChemInform, 2006Co-Authors: Taichi Kano, Takuya Hashimoto, Keiji MaruokaAbstract:A μ-oxo-type chiral bis-Ti(IV) oxide (S,S)-1 can be successfully utilized in the asymmetric 1,3-dipolar cycloaddition reactions between various Nitrones 2 and acrolein to give the corresponding isoxazolidines with high to excellent enantioselectivities. For instance, the reaction between Nitrone 2 (R = t-Bu) and acrolein in the presence of 10 mol % of bis-Ti(IV) catalyst (S,S)-1 in dichloromethane at −40 °C gave the corresponding endo cycloadduct with 97% ee.
