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Kent S Gates - One of the best experts on this subject based on the ideXlab platform.
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On the Reaction Mechanism of Tirapazamine Reduction Chemistry: Unimolecular N–OH Homolysis, Stepwise Dehydration, or Triazene Ring-Opening
2016Co-Authors: Jian Yin, Rainer Glaser, Kent S GatesAbstract:The initial steps of the activation of tirapazamine (TPZ, 1, 3-amino-1,2,4-benzotriazine 1,4-N,N-dioxide) under hypoxic conditions consist of the one-electron Reduction of 1 to radical anion 2 and the protonation of 2 at O(N4) or O(N1) to form neutral radicals 3 and 4, respectively. There are some questions, however, as to whether radicals 3 and/or 4 will then undergo N–OH homolyses 3 → 5 + ·OH and 4 → 6 + ·OH or, alternatively, whether 3 and/or 4 may react by dehydration and form aminyl radicals via 3 → 11 + H2O and 4 → 12 + H2O or phenyl radicals via 3 → 17 + H2O. These outcomes might depend on the Chemistry after the homolysis of 3 and/or 4, that is, dehydration may be the result of a two-step sequence that involves N–OH homolysis and formation of ·OH aggregates of 5 and 6 followed by H-abstraction within the ·OH aggregates to form hydrates of aminyls 11 and 12 or of phenyl 17. We studied these processes with configuration interaction theory, perturbation theory, and density functional theory. All stationary structures of OH aggregates of 5 and 6, of H2O aggregates of 11, 12, and 17, and of the transition state structures for H-abstraction were located and characterized by vibrational analysis and with methods of electron and spin-density analysis. The doublet radical 17 is a normal spin-polarized radical, whereas the doublet radicals 11 and 12 feature quartet instabilities. The computed reaction energies and activation barriers allow for dehydration in principle, but the productivity of all of these channels should be low for kinetic and dynamic reasons. With a view to plausible scenarios for the generation of latent aryl radical species without dehydration, we scanned the potential energy surfaces of 2–4 as a function of the (O)N1–Y (Y = C5a, N2) and (O)N4–Z (Z = C4a, C3) bond lengths. The elongation of any one of these bonds by 0.5 Å requires less than 25 kcal/mol, and this finding strongly suggests the possibility of bimolecular reactions of the spin-trap molecules with 2–4 concomitant with triazene ring-opening
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on the reaction mechanism of tirapazamine Reduction Chemistry unimolecular n oh homolysis stepwise dehydration or triazene ring opening
Chemical Research in Toxicology, 2012Co-Authors: Jian Yin, Rainer Glaser, Kent S GatesAbstract:The initial steps of the activation of tirapazamine (TPZ, 1, 3-amino-1,2,4-benzotriazine 1,4-N,N-dioxide) under hypoxic conditions consist of the one-electron Reduction of 1 to radical anion 2 and the protonation of 2 at O(N4) or O(N1) to form neutral radicals 3 and 4, respectively. There are some questions, however, as to whether radicals 3 and/or 4 will then undergo N–OH homolyses 3 → 5 + ·OH and 4 → 6 + ·OH or, alternatively, whether 3 and/or 4 may react by dehydration and form aminyl radicals via 3 → 11 + H2O and 4 → 12 + H2O or phenyl radicals via 3 → 17 + H2O. These outcomes might depend on the Chemistry after the homolysis of 3 and/or 4, that is, dehydration may be the result of a two-step sequence that involves N–OH homolysis and formation of ·OH aggregates of 5 and 6 followed by H-abstraction within the ·OH aggregates to form hydrates of aminyls 11 and 12 or of phenyl 17. We studied these processes with configuration interaction theory, perturbation theory, and density functional theory. All stat...
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Electron and Spin-Density Analysis of Tirapazamine Reduction Chemistry
2012Co-Authors: Jian Yin, Rainer Glaser, Kent S GatesAbstract:Tirapazamine (TPZ, 1, 3-amino-1,2,4-benzotriazine 1,4-N,N-dioxide), the radical anion 2 formed by one-electron Reduction of 1, and neutral radicals 3 and 4 formed by protonation of 2 at O(N4) or O(N1), respectively, and their N–OH homolyses 3 → 5 + ·OH and 4 → 6 + ·OH have been studied with configuration interaction theory, perturbation theory, and density functional theory. A comprehensive comparative analysis is presented of structures and electronic structures and with focus on the development of an understanding of the spin-density distributions of the radical species. The skeletons of radicals 3 and 4 are distinctly nonplanar, several stereoisomeric structures are discussed, and there exists an intrinsic preference for 3 over 4. The N-oxides 1, 5, and 6 have closed-shell singlet ground states and low-lying, singlet biradical (SP-1, SP-6) or biradicaloid (SP-5) excited states. The doublet radicals 2, 3, and 4 are heavily spin-polarized. Most of the spin density of the doublet radicals 2, 3, and 4 is located in one (N,O)-region, and in particular, 3 and 4 are not C3-centered radicals. Significant amounts of spin density occur in both rings in the singlet biradical(oid) excited states of 1, 5, and 6. The dipole moment of the N2–C3(X) bond is large, and the nature of X provides a powerful handle to modulate the N2–C3 bond polarity with opposite effects on the two NO regions. Our studies show very low proton affinities of radical anion 2 and suggest that the pKa of radical [2+H] might be lower than 6. Implications are discussed regarding the formation of hydroxyl from 3 and/or 4, regarding the ability of 5 and 6 to react with carbon-centered radicals in a manner that ultimately leads to oxygen transfer, and regarding the interpretation of the EPR spectra of reduced TPZ species and of their spin-trap adducts
James A. Dumesic - One of the best experts on this subject based on the ideXlab platform.
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exploring meerwein ponndorf verley Reduction Chemistry for biomass catalysis using a first principles approach
ACS Catalysis, 2013Co-Authors: Rajeev S. Assary, Larry A. Curtiss, James A. DumesicAbstract:Liquid phase catalytic hydrogenation of decomposition products of sugar molecules is challenging, but essential to produce platform chemicals and green chemicals from biomass. The Meerwein–Ponndorf–Verley (MPV) Reduction Chemistry is an excellent choice for the hydrogenation of keto compounds. The energy landscapes for the liquid phase catalytic hydrogenation of ethyl levulinate (EL) and furfural (FF) by Sn(IV) and Zr(IV) zeolite-like catalytic sites utilizing the hydrogen atoms from an isopropanol (IPA) solvent are explored using quantum chemical methods. The computed apparent activation free energy for the catalytic hydrogenation of EL by a Sn(IV) zeolite-like catalyst model site is (21.9 kcal/mol), which is close to the Al(III)-isopropoxide catalyzed (20.7 kcal/mol) EL hydrogenation indicating the similar efficiency of the Sn(IV) zeolite-like catalyst compared with the Al(III) catalyst used in the traditional MPV reactions. The catalytic efficiency of metal isopropoxides for the catalytic hydrogenation...
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Exploring Meerwein–Ponndorf–Verley Reduction Chemistry for Biomass Catalysis Using a First-Principles Approach
2013Co-Authors: Rajeev S. Assary, Larry A. Curtiss, James A. DumesicAbstract:Liquid phase catalytic hydrogenation of decomposition products of sugar molecules is challenging, but essential to produce platform chemicals and green chemicals from biomass. The Meerwein–Ponndorf–Verley (MPV) Reduction Chemistry is an excellent choice for the hydrogenation of keto compounds. The energy landscapes for the liquid phase catalytic hydrogenation of ethyl levulinate (EL) and furfural (FF) by Sn(IV) and Zr(IV) zeolite-like catalytic sites utilizing the hydrogen atoms from an isopropanol (IPA) solvent are explored using quantum chemical methods. The computed apparent activation free energy for the catalytic hydrogenation of EL by a Sn(IV) zeolite-like catalyst model site is (21.9 kcal/mol), which is close to the Al(III)-isopropoxide catalyzed (20.7 kcal/mol) EL hydrogenation indicating the similar efficiency of the Sn(IV) zeolite-like catalyst compared with the Al(III) catalyst used in the traditional MPV reactions. The catalytic efficiency of metal isopropoxides for the catalytic hydrogenation of EL is computed to be Al(III) > Sn(IV) > Zr(IV) in IPA solution, in agreement with experiment. Calculations were also performed with furfuryl alcohol as the source for hydrogen for the conversion of EL to γ-valerolactone using the Sn(IV) catalytic site. The barrier (22.7 kcal/mol) suggests a hydrogenation using aromatic primary alcohol as a hydrogen donor and using a Sn(IV) catalyst is feasible. In terms of reaction mechanisms, an intramolecular hydride transfer through a six membered transition state was found to be the turnover controlling transition state of liquid phase catalytic hydrogenation of carbonyl compounds considered in this study
Ahmed Ashour Ahmed - One of the best experts on this subject based on the ideXlab platform.
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subtraction free and bisulfite free specific sequencing of 5 methylcytosine and its oxidized derivatives at base resolution
Nature Communications, 2021Co-Authors: Yibin Liu, Jingfei Cheng, Paulina Siejkazielinska, Jinfeng Chen, Masato Inoue, Ahmed Ashour AhmedAbstract:Although various methods have been developed for sequencing cytosine modifications, it is still challenging for specific and quantitative sequencing of individual modification at base-resolution. For example, to obtain both true 5-methylcytosine (5mC) and true 5-hydroxymethylcytosine (5hmC) information, the two major epigenetic modifications, it usually requires subtraction of two methods, which increases noise and requires high sequencing depth. Recently, we developed TET-assisted pyridine borane sequencing (TAPS) for bisulfite-free direct sequencing of 5mC and 5hmC. Here we demonstrate that two sister methods, TAPSβ and chemical-assisted pyridine borane sequencing (CAPS), can be effectively used for subtraction-free and specific whole-genome sequencing of 5mC and 5hmC, respectively. We also demonstrate pyridine borane sequencing (PS) for whole-genome profiling of 5-formylcytosine and 5-carboxylcytosine, the further oxidized derivatives of 5mC and 5hmC. This work completes the set of versatile borane Reduction Chemistry-based methods as a comprehensive toolkit for direct and quantitative sequencing of all four cytosine epigenetic modifications.
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subtraction free and bisulfite free specific sequencing of 5 methylcytosine and its oxidized derivatives at base resolution
Nature Communications, 2021Co-Authors: Yibin Liu, Jingfei Cheng, Paulina Siejkazielinska, Jinfeng Chen, Masato Inoue, Ahmed Ashour AhmedAbstract:Although various methods have been developed for sequencing cytosine modifications, it is still challenging for specific and quantitative sequencing of individual modification at base-resolution. For example, to obtain both true 5-methylcytosine (5mC) and true 5-hydroxymethylcytosine (5hmC) information, the two major epigenetic modifications, it usually requires subtraction of two methods, which increases noise and requires high sequencing depth. Recently, we developed TET-assisted pyridine borane sequencing (TAPS) for bisulfite-free direct sequencing of 5mC and 5hmC. Here we demonstrate that two sister methods, TAPSβ and chemical-assisted pyridine borane sequencing (CAPS), can be effectively used for subtraction-free and specific whole-genome sequencing of 5mC and 5hmC, respectively. We also demonstrate pyridine borane sequencing (PS) for whole-genome profiling of 5-formylcytosine and 5-carboxylcytosine, the further oxidized derivatives of 5mC and 5hmC. This work completes the set of versatile borane Reduction Chemistry-based methods as a comprehensive toolkit for direct and quantitative sequencing of all four cytosine epigenetic modifications. Specific and quantitative sequencing of cytosine modifications is challenging at base-resolution. Here the authors present TAPSβ and CAPS for subtraction-free whole genome sequencing of 5mC and 5hmC.
Jinfeng Chen - One of the best experts on this subject based on the ideXlab platform.
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subtraction free and bisulfite free specific sequencing of 5 methylcytosine and its oxidized derivatives at base resolution
Nature Communications, 2021Co-Authors: Yibin Liu, Jingfei Cheng, Paulina Siejkazielinska, Jinfeng Chen, Masato Inoue, Ahmed Ashour AhmedAbstract:Although various methods have been developed for sequencing cytosine modifications, it is still challenging for specific and quantitative sequencing of individual modification at base-resolution. For example, to obtain both true 5-methylcytosine (5mC) and true 5-hydroxymethylcytosine (5hmC) information, the two major epigenetic modifications, it usually requires subtraction of two methods, which increases noise and requires high sequencing depth. Recently, we developed TET-assisted pyridine borane sequencing (TAPS) for bisulfite-free direct sequencing of 5mC and 5hmC. Here we demonstrate that two sister methods, TAPSβ and chemical-assisted pyridine borane sequencing (CAPS), can be effectively used for subtraction-free and specific whole-genome sequencing of 5mC and 5hmC, respectively. We also demonstrate pyridine borane sequencing (PS) for whole-genome profiling of 5-formylcytosine and 5-carboxylcytosine, the further oxidized derivatives of 5mC and 5hmC. This work completes the set of versatile borane Reduction Chemistry-based methods as a comprehensive toolkit for direct and quantitative sequencing of all four cytosine epigenetic modifications.
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subtraction free and bisulfite free specific sequencing of 5 methylcytosine and its oxidized derivatives at base resolution
Nature Communications, 2021Co-Authors: Yibin Liu, Jingfei Cheng, Paulina Siejkazielinska, Jinfeng Chen, Masato Inoue, Ahmed Ashour AhmedAbstract:Although various methods have been developed for sequencing cytosine modifications, it is still challenging for specific and quantitative sequencing of individual modification at base-resolution. For example, to obtain both true 5-methylcytosine (5mC) and true 5-hydroxymethylcytosine (5hmC) information, the two major epigenetic modifications, it usually requires subtraction of two methods, which increases noise and requires high sequencing depth. Recently, we developed TET-assisted pyridine borane sequencing (TAPS) for bisulfite-free direct sequencing of 5mC and 5hmC. Here we demonstrate that two sister methods, TAPSβ and chemical-assisted pyridine borane sequencing (CAPS), can be effectively used for subtraction-free and specific whole-genome sequencing of 5mC and 5hmC, respectively. We also demonstrate pyridine borane sequencing (PS) for whole-genome profiling of 5-formylcytosine and 5-carboxylcytosine, the further oxidized derivatives of 5mC and 5hmC. This work completes the set of versatile borane Reduction Chemistry-based methods as a comprehensive toolkit for direct and quantitative sequencing of all four cytosine epigenetic modifications. Specific and quantitative sequencing of cytosine modifications is challenging at base-resolution. Here the authors present TAPSβ and CAPS for subtraction-free whole genome sequencing of 5mC and 5hmC.
Paulina Siejkazielinska - One of the best experts on this subject based on the ideXlab platform.
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subtraction free and bisulfite free specific sequencing of 5 methylcytosine and its oxidized derivatives at base resolution
Nature Communications, 2021Co-Authors: Yibin Liu, Jingfei Cheng, Paulina Siejkazielinska, Jinfeng Chen, Masato Inoue, Ahmed Ashour AhmedAbstract:Although various methods have been developed for sequencing cytosine modifications, it is still challenging for specific and quantitative sequencing of individual modification at base-resolution. For example, to obtain both true 5-methylcytosine (5mC) and true 5-hydroxymethylcytosine (5hmC) information, the two major epigenetic modifications, it usually requires subtraction of two methods, which increases noise and requires high sequencing depth. Recently, we developed TET-assisted pyridine borane sequencing (TAPS) for bisulfite-free direct sequencing of 5mC and 5hmC. Here we demonstrate that two sister methods, TAPSβ and chemical-assisted pyridine borane sequencing (CAPS), can be effectively used for subtraction-free and specific whole-genome sequencing of 5mC and 5hmC, respectively. We also demonstrate pyridine borane sequencing (PS) for whole-genome profiling of 5-formylcytosine and 5-carboxylcytosine, the further oxidized derivatives of 5mC and 5hmC. This work completes the set of versatile borane Reduction Chemistry-based methods as a comprehensive toolkit for direct and quantitative sequencing of all four cytosine epigenetic modifications.
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subtraction free and bisulfite free specific sequencing of 5 methylcytosine and its oxidized derivatives at base resolution
Nature Communications, 2021Co-Authors: Yibin Liu, Jingfei Cheng, Paulina Siejkazielinska, Jinfeng Chen, Masato Inoue, Ahmed Ashour AhmedAbstract:Although various methods have been developed for sequencing cytosine modifications, it is still challenging for specific and quantitative sequencing of individual modification at base-resolution. For example, to obtain both true 5-methylcytosine (5mC) and true 5-hydroxymethylcytosine (5hmC) information, the two major epigenetic modifications, it usually requires subtraction of two methods, which increases noise and requires high sequencing depth. Recently, we developed TET-assisted pyridine borane sequencing (TAPS) for bisulfite-free direct sequencing of 5mC and 5hmC. Here we demonstrate that two sister methods, TAPSβ and chemical-assisted pyridine borane sequencing (CAPS), can be effectively used for subtraction-free and specific whole-genome sequencing of 5mC and 5hmC, respectively. We also demonstrate pyridine borane sequencing (PS) for whole-genome profiling of 5-formylcytosine and 5-carboxylcytosine, the further oxidized derivatives of 5mC and 5hmC. This work completes the set of versatile borane Reduction Chemistry-based methods as a comprehensive toolkit for direct and quantitative sequencing of all four cytosine epigenetic modifications. Specific and quantitative sequencing of cytosine modifications is challenging at base-resolution. Here the authors present TAPSβ and CAPS for subtraction-free whole genome sequencing of 5mC and 5hmC.