Transfer Radical Research Articles

Risk of Excess Maternal Folic Acid Supplementation in Offspring.

Folate, also known as vitamin B9, facilitates the transfer of methyl groups among molecules, which is crucial for amino acid metabolism and nucleotide synthesis. Adequate maternal folate supplementation has been widely acknowledged for its pivotal role in promoting cell proliferation and preventing neural tube defects. However, in the post-fortification era, there has been a rising concern regarding an excess maternal intake of folic acid (FA), the synthetic form of folate. In this review, we focused on recent advancements in understanding the influence of excess maternal FA intake on offspring. For human studies, we summarized findings from clinical trials investigating the effects of periconceptional FA intake on neurodevelopment and molecular-level changes in offspring. For studies using mouse models, we compiled the impact of high maternal FA supplementation on gene expression and behavioral changes in offspring. In summary, excessive maternal folate intake could potentially have adverse effects on offspring. Overall, we highlighted concerns regarding elevated maternal folate status in the population, providing a comprehensive perspective on the potential adverse effects of excessive maternal FA supplementation on offspring.

Unexpected transamination between 2-aminoazoles and N-iodoacetyl azoles

N-Iodoacetyl-substituted azoles undergo transfer of iodoacetyl group from heterocyclic N atom toward the amino group of amino azoles, unlike the earlier investigated iodomethyl ketones. The proposed mechanism explaining the observed difference in such transamination is confirmed by calculations. The product derived from 2-aminobenzimidazole is cyclized into fused imidazo[1,2-α]benzimidazol- 9-ium salt.

A new type of sulfation reaction: C-sulfonation for α,β-unsaturated carbonyl groups by a novel sulfotransferase SULT7A1.

Cytosolic sulfotransferases (SULTs) are cytosolic enzymes that catalyze the transfer of sulfonate group to key endogenous compounds, altering the physiological functions of their substrates. SULT enzymes catalyze the O-sulfonation of hydroxy groups or N-sulfonation of amino groups of substrate compounds. In this study, we report the discovery of C-sulfonation of α,β-unsaturated carbonyl groups mediated by a new SULT enzyme, SULT7A1, and human SULT1C4. Enzymatic assays revealed that SULT7A1 is capable of transferring the sulfonate group from 3'-phosphoadenosine 5'-phosphosulfate to the α-carbon of α,β-unsaturated carbonyl-containing compounds, including cyclopentenone prostaglandins as representative endogenous substrates. Structural analyses of SULT7A1 suggest that the C-sulfonation reaction is catalyzed by a novel mechanism mediated by His and Cys residues in the active site. Ligand-activity assays demonstrated that sulfonated 15-deoxy prostaglandin J2 exhibits antagonist activity against the prostaglandin receptor EP2 and the prostacyclin receptor IP. Modification of α,β-unsaturated carbonyl groups via the new prostaglandin-sulfonating enzyme, SULT7A1, may regulate the physiological function of prostaglandins in the gut. Discovery of C-sulfonation of α,β-unsaturated carbonyl groups will broaden the spectrum of potential substrates and physiological functions of SULTs.

Polyamine Inhibitor SAM486A Augments Cytarabine Cytotoxicity in Methylthioadenosine Phosphorylase-deficient Leukemia Cells.

Methionine metabolism contributes to supplying sulfur-containing amino acids, controlling the methyl group transfer reaction, and producing polyamines in cancer cells. Polyamines play important roles in various cellular functions. Methylthioadenosine phosphorylase (MTAP), the key enzyme of the methionine salvage pathway, is reported to be deficient in 15-62% of cases of hematological malignancies. MTAP-deficient cancer cells accumulate polyamines, resulting in enhanced cell proliferation. The aim of this study was to investigate the combined effects of the polyamine synthesis inhibitor SAM486A and the anticancer antimetabolite cytarabine in MTAP-deficient leukemic cells in vitro. The leukemia cell line U937 and the subline, U937/MTAP(-), in which MTAP was knocked down by shRNA, were used. The experiments were performed in media supplemented with 20% methionine (low methionine), which was the minimum concentration for maintaining cellular viability. The knockdown efficiency test confirmed a 70% suppression of the expression of the MTAP gene in U937/MTAP(-) cells. Even in the media with low methionine, the intracellular methionine concentration was not reduced in U937/MTAP(-) cells, suggesting that the minimum supply of methionine was sufficient to maintain intracellular levels of methionine. Both U937/MTAP(+) and U937/MTAP(-) cells were comparably sensitive to anticancer drugs (cytarabine, methotrexate, clofarabine and 6-thioguanine). The combination of SAM486A and cytarabine was demonstrated to have synergistic cytotoxicity in U937/MTAP(-) cells with regard to cell growth inhibition and apoptosis induction, but not in U937/MTAP(+) cells. Mechanistically, SAM486A altered the intracellular polyamine concentrations and reduced the antiapoptotic proteins. Methionine metabolism and polyamine synthesis can be attractive therapeutic targets in leukemia.

Simple Functionalization of a Donor Monomer to Enhance Charge Transfer in Porous Polymer Networks for Photocatalytic Hydrogen Evolution.

Porous polymer networks (PPNs) are promising candidates as photocatalysts for hydrogen production. Constructing a donor-acceptor structure is known to be an effective approach for improving photocatalytic activity. However, the process of how a functional group of a monomer can ensure photoexcited charges transfer and improve the hydrogen evolution rate (HER) has not yet been studied on the molecular level. Herein, we design and synthesize two kinds of triazatruxene (TAT)-based PPNs: TATR-PPN with a hexyl (R) group and TAT-PPN without the hexyl group, to understand the relationship between the presence of the functional group and charge transfer. The hexyl group on the TAT unit was found to ensure the transfer of photoexcited electrons from a donor unit to an acceptor unit and endowed the TATR-PPN with stable hydrogen production.

Effect of repeated vitrification of human embryos on pregnancy and neonatal outcomes

BackgroundRepeated cryopreservation of embryos should occasionally be considered when embryos were not suitable for transfer. The effect of re-cryopreservation on embryos remains contentious.MethodsThis retrospective cohort study aimed to evaluate the pregnancy and neonatal outcomes of twice vitrificated blastocyst derived from once vitrified embryos. Total 410 vitrified-warmed blastocyst transfer cycles were divided into two groups according to the times of embryo vitrification: (1) vitrified blastocysts derived from fresh blastocysts (control group, n = 337); (2) twice vitrified blastocysts derived from once vitrified embryos (n = 73). The primary outcome was live birth rate. Multivariable logistic or linear regression analysis model was performed to describe the association between embryo cryopreservation times and clinical outcomes.ResultsNo difference was observed in female age at retrieval and transfer, infertility period, body mass index (BMI), infertility type, endometrial thickness, and embryo transfer numbers between the two groups. The pregnancy outcomes of embryos in repeated cryopreservation group were comparable to those of embryos in control group, including implantation rate, clinical pregnancy rate, and live birth rate. In multivariate logistic regression analysis, the cryopreservation times did not affect the outcomes of biochemical pregnancy, clinical pregnancy, and live birth. Moreover, there was no difference in gestational age, birthweight and sex ratio of singleton newborns between groups. After correcting several possible confounding variables, no significant association was observed between cryopreservation times and neonatal birthweight.ConclusionIn conclusion, pregnancy and neonatal outcomes achieved with twice vitrified blastocyst transfer were comparable to those achieved with vitrified blastocyst transfer in control group.

Nitrogen-doped ordered mesoporous carbon supported ruthenium metallic nanoparticles: Opportunity for efficient hydrogenolysis of biomass-derived 5-hydroxymethylfurfural to 2,5-dimethylfuran by catalytic transfer hydrogenation

One of the most promising solutions to the current energy crisis is an efficient catalytic transformation of abundant low-cost renewable raw biomass into high-quality biofuel. Herein, a highly effective catalyst was constructed systematically for the selective synthesis of 2,5-dimethylfuran (DMF) biofuel from biomass-derived 5-hydroxymethylfurfural (HMF) via green catalytic transfer hydrogenolysis (CTH) using a nitrogen-doped ordered mesoporous carbon (N-CMK-1) decorated ruthenium (Ru)-based catalyst in i-propanol as hydrogen source. The structures and properties of different catalysts were characterized by different characterization techniques such as FTIR, XRD, N2-sorption, CO2-sorption, TGA, TEM, ICP-AES, CHNO analysis, and acid-base back titration. A complete HMF conversion with a high DMF yield of 88% was achieved under optimized reaction conditions. Regarding substrate conversion and product yield, the influence of reaction temperature, time, and hydrogen donors was thoroughly investigated. The nitrogen-promoted carbon support enhanced the dispersion of Ru due to the formation of appropriate basic site density which could efficiently promote the activation of alcohol hydroxyl in i-propanol and subsequent release of active hydrogen species. In the meantime, highly dispersed surface Ru nanoparticles (NPs) were beneficial for hydrogen transfer and activation of both carbonyl and hydroxyl groups in HMF. Moreover, Arrhenius kinetic analysis was studied by identifying 5-methyl furfural (5-MF) and 2,5-bishydroxymethylfuran (BHMF) as two key intermediates that dominate a distinct reaction pathway during hydrogenolysis of HMF to DMF via CTH. Furthermore, high stability without obvious loss of activity after three consecutive cycles was observed in a fabricated N-CMK-1 decorated Ru-based catalyst as a result of superior metal-support interaction and the mesoporous framework nature of the catalyst. These findings would not only offer a robust catalyst synthetic approach but also open a new avenue for the exploitation of biomass to specialty chemicals and advanced biofuels.

Accessing Highly Substituted Indoles via B(C6F5)3-Catalyzed Secondary Alkyl Group Transfer.

Herein, we report a synthetic method to access a range of highly substituted indoles via the B(C6F5)3-catalyzed transfer of 2° alkyl groups from amines. The transition-metal-free catalytic approach has been demonstrated across a broad range of indoles and amine 2° alkyl donors, including various substituents on both reacting components, to access useful C(3)-alkylated indole products. The alkyl transfer process can be performed using Schlenk line techniques in combination with commercially available B(C6F5)3·nH2O and solvents, which obviates the requirement for specialized equipment (e.g., glovebox).

Protein pyrophosphorylation by inositol phosphates: a novel post-translational modification in plants?

Inositol pyrophosphates (PP-InsPs) are energy-rich molecules harboring one or more diphosphate moieties. PP-InsPs are found in all eukaryotes evaluated and their functional versatility is reflected in the various cellular events in which they take part. These include, among others, insulin signaling and intracellular trafficking in mammals, as well as innate immunity and hormone and phosphate signaling in plants. The molecular mechanisms by which PP-InsPs exert such functions are proposed to rely on the allosteric regulation via direct binding to proteins, by competing with other ligands, or by protein pyrophosphorylation. The latter is the focus of this review, where we outline a historical perspective surrounding the first findings, almost 20 years ago, that certain proteins can be phosphorylated by PP-InsPs in vitro. Strikingly, in vitro phosphorylation occurs by an apparent enzyme-independent but Mg2+-dependent transfer of the β-phosphoryl group of an inositol pyrophosphate to an already phosphorylated serine residue at Glu/Asp-rich protein regions. Ribosome biogenesis, vesicle trafficking and transcription are among the cellular events suggested to be modulated by protein pyrophosphorylation in yeast and mammals. Here we discuss the latest efforts in identifying targets of protein pyrophosphorylation, pointing out the methodological challenges that have hindered the full understanding of this unique post-translational modification, and focusing on the latest advances in mass spectrometry that finally provided convincing evidence that PP-InsP-mediated pyrophosphorylation also occurs in vivo. We also speculate about the relevance of this post-translational modification in plants in a discussion centered around the protein kinase CK2, whose activity is critical for pyrophosphorylation of animal and yeast proteins. This enzyme is widely present in plant species and several of its functions overlap with those of PP-InsPs. Until now, there is virtually no data on pyrophosphorylation of plant proteins, which is an exciting field that remains to be explored.

Visible-Light-Driven Unsymmetric gem-Difunctionalization of Vinyl Azides with Thiosulfonates or Selenosulfonates.

Thiosulfonylation and selenosulfonylation of vinyl azides with thiosulfonates and selenosulfonates were achieved using Cu(dap)2Cl as a photosensitizer under visible-light irradiation. This reaction is the application of a vinyl azide substrate in a group transfer radical addition (GTRA) reaction, through β-difunctionalization, to obtain a variety of unsymmetric difunctionalized N-unprotected enamines.

Photocatalytic Carbamoyl Radical Transfer to Alkenyl Azaarenes

Abstract1-Phenyl-3-azaarenyl-propan-1-amine structural moieties have been widely incorporated in pharmaceuticals and biologically active compounds; however, current synthetic methods to access these compounds need multiple steps and proceed with low efficiency. Herein, we reported an efficient photocatalytic carbamoyl radical transfer approach that allows the preparation of these compounds in high yields (up to 88%). The reaction easily runs on a gram-scale and was applied for the preparation of pheniramine in two steps with 72% total yield.

Review and Theoretical Analysis of Fluorinated Radicals in Direct CAr−H Functionalization of (Hetero)arenes

AbstractWe highlight key contributions in the field of direct radical CAr− H (hetero)aromatic functionalization involving fluorinated radicals. A compilation of Functional Group Transfer Reagents and their diverse activation mechanisms leading to the release of radicals are discussed. The substrate scope for each radical is analyzed and classified into three categories according to the electronic properties of the substrates. Density functional theory computational analysis provides insights into the chemical reactivity of several fluorinated radicals through their electrophilicity and nucleophilicity parameters. Theoretical analysis of their reduction potentials also highlights the remarkable correlation between electrophilicity and oxidizing ability. It is also established that highly fluorinated radicals (e.g. ⋅OCF3) are capable of engaging in single‐electron transfer (SET) processes rather than radical addition, which is in good agreement with experimental literature data. A reactivity scale, based on activation barrier of addition of these radicals to benzene is also elaborated using the high accuracy DLPNO‐(U)CCSD(T) method.

Engineering Methacrylic Block Copolymers by Organic Catalysis Group Transfer Polymerization-Induced Self-Assembly in Nonpolar Media at Room Temperature

Engineering Methacrylic Block Copolymers by Organic Catalysis Group Transfer Polymerization-Induced Self-Assembly in Nonpolar Media at Room Temperature

Review and Theoretical Analysis of Fluorinated Radicals in Direct CAr-H Functionalization of (Hetero)arenes.

We highlight key contributions in the field of direct radical CAr- H (hetero)aromatic functionalization involving fluorinated radicals. A compilation of Functional Group Transfer Reagents and their diverse activation mechanisms leading to the release of radicals are discussed. The substrate scope for each radical is analyzed and classified into three categories according to the electronic properties of the substrates. Density functional theory computational analysis provides insights into the chemical reactivity of several fluorinated radicals through their electrophilicity and nucleophilicity parameters. Theoretical analysis of their reduction potentials also highlights the remarkable correlation between electrophilicity and oxidizing ability. It is also established that highly fluorinated radicals (e.g. ⋅OCF3) are capable of engaging in single-electron transfer (SET) processes rather than radical addition, which is in good agreement with experimental literature data. A reactivity scale, based on activation barrier of addition of these radicals to benzene is also elaborated using the high accuracy DLPNO-(U)CCSD(T) method.

Photo‐Induced Disproportionation‐Mediated Photodynamic Therapy: Simultaneous Oxidation of Tetrahydrobiopterin and Generation of Superoxide Radicals

AbstractWe herein present an approach of photo‐induced disproportionation for preparation of Type‐I photodynamic agents. As a proof of concept, BODIPY‐based photosensitizers were rationally designed and prepared. The photo‐induced intermolecular electron transfer between homotypic chromophores leads to the disproportionation reaction, resulting in the formation of charged intermediates, cationic and anionic radicals. The cationic radicals efficiently oxidize the cellularimportant coenzyme, tetrahydrobiopterin (BH4), and the anionic radicals transfer electrons to oxygen to produce superoxide radicals (O2−⋅). One of our Type‐I photodynamic agents not only self‐assembles in water but also effectively targets the endoplasmic reticulum. It displayed excellent photocytotoxicity even in highly hypoxic environments (2 % O2), with a half‐maximal inhibitory concentration (IC50) of 0.96 μM, and demonstrated outstanding antitumor efficacy in murine models bearing HeLa tumors.

Photo-Induced Disproportionation-Mediated Photodynamic Therapy: Simultaneous Oxidation of Tetrahydrobiopterin and Generation of Superoxide Radicals.

We herein present an approach of photo-induced disproportionation for preparation of Type-I photodynamic agents. As a proof of concept, BODIPY-based photosensitizers were rationally designed and prepared. The photo-induced intermolecular electron transfer between homotypic chromophores leads to the disproportionation reaction, resulting in the formation of charged intermediates, cationic and anionic radicals. The cationic radicals efficiently oxidize the cellularimportant coenzyme, tetrahydrobiopterin (BH4 ), and the anionic radicals transfer electrons to oxygen to produce superoxide radicals (O2 - ⋅). One of our Type-I photodynamic agents not only self-assembles in water but also effectively targets the endoplasmic reticulum. It displayed excellent photocytotoxicity even in highly hypoxic environments (2 % O2 ), with a half-maximal inhibitory concentration (IC50 ) of 0.96 μM, and demonstrated outstanding antitumor efficacy in murine models bearing HeLa tumors.

PH-dependent and whole-cell catalytic decolorization of dyes using recombinant dye-decolorizing peroxidase from Rhodococcus jostii.

Dyes in wastewater have adverse effects on the environment and human health. Dye-decolorizing peroxidase (DyP) is a promising biocatalyst to dyes degradation, but the decolorization rates varied greatly which influencing factors and mechanisms remain to be fully disclosed. To explore an effective decolorizing approach, we have studied a DyP from Rhodococcus jostii (RhDyPB) which was overexpressed in Escherichia coli to decolorize four kinds of dyes, Reactive blue 19, Eosin Y, Indigo carmine, and Malachite green. We found the decolorization rates of the dyes by purified RhDyPB were all pH-dependent and the highest one was 94.4% of Malachite green at pH 6.0. ESI-MS analysis of intermediates in the decolorization process of Reactive blue 19 proved the degradation was due to peroxidase catalysis. Molecular docking predicated the interaction of RhDyPB with dyes, and a radical transfer reaction. In addition, we performed decolorization of dyes with whole E. coli cell with and without expressing RhDyPB. It was found that decolorization of dyes by E. coli cell wasdue to both cell absorption and degradation, and RhDyPB expression improved the degradation rates towards Reactive blue 19, Indigo carmine and Malachite green. The effective decolorization of Malachite green and the successful application of whole DyP-overexpressed cells in dye decolorization is conducive to the bioremediation of dye-containing wastewaters by DyPs.

Probing Nonadiabaticity of Proton-Coupled Electron Transfer in Ribonucleotide Reductase.

The enzyme ribonucleotide reductase, which is essential for DNA synthesis, initiates the conversion of ribonucleotides to deoxyribonucleotides via radical transfer over a 32 Å pathway composed of proton-coupled electron transfer (PCET) reactions. Previously, the first three PCET reactions in the α subunit were investigated with hybrid quantum mechanical/molecular mechanical (QM/MM) free energy simulations. Herein, the fourth PCET reaction in this subunit between C439 and guanosine diphosphate (GDP) is simulated and found to be slightly exoergic with a relatively high free energy barrier. To further elucidate the mechanisms of all four PCET reactions, we analyzed the vibronic and electron-proton nonadiabaticities. This analysis suggests that interfacial PCET between Y356 and Y731 is vibronically and electronically nonadiabatic, whereas PCET between Y731 and Y730 and between C439 and GDP is fully adiabatic and PCET between Y730 and C439 is in the intermediate regime. These insights provide guidance for selecting suitable rate constant expressions for these PCET reactions.

Extending the Scope of Conceptual Density Functional Theory with Second Order Analytical Methodologies.

In the context of the growing impact of conceptual density functional theory (DFT) as one of the most successful chemical reactivity theories, response functions up to second order have now been widely applied; in recent years, among others, particular attention has been focused on the linear response function and also extensions to higher order have been put forward. As the larger part of these studies have been carried using a finite difference approach to compute these concepts, we now embarked on (an extension of) an analytical approach to conceptual DFT. With the ultimate aim of providing a complete set of analytically computable second order properties, including the softness and hardness kernels, the hardness as the simplest second order response function is scrutinized again with numerical results highlighting the difference in nature between the analytical hardness (referred to as hardness condition) and the Parr-Pearson absolute chemical hardness. The hardness condition is investigated for its capability to gauge the (de)localization error of density functional approximations (DFAs). The analytical Fukui function, besides overcoming the difficulties in the finite difference approach in treating negatively charged systems, also showcases the errors of deviating from the straight-line behavior using fractional occupation number calculations. Subsequently, the softness kernel and its atom-condensed inverse, the hardness matrix, are accessed through the Berkowitz-Parr relation. Revisiting the softness kernel confirms and extends previous discussions on how Kohn's Nearsightedness of Electronic Matter principle can be retrieved and identified as the physicist's version of the chemist's "transferability of functional groups" concept. The accurate, analytical hardness matrix evaluation on the other hand provides further support for the basics of Nalewajski's charge sensitivity analysis. Based on Parr and Liu's functional expansion of the energy functional, a new energy decomposition is introduced with an order of magnitude analysis of the different terms for a series of simple molecules both at their equilibrium geometry and upon variation in bond length and dihedral angle. Finally, for the first time, the perturbation expansion of the energy functional is studied numerically up to second order now that all response functions and integration techniques are at hand. The perturbation expansion energies are in excellent agreement with those obtained directly from DFA calculations giving confidence in the convergence of the perturbation series and its use in judging the importance of the different terms in reactivity investigations.

Tricoordinate Beryllium Radicals and Their Reactivity.

The one-electron reduction of [(CAAC)Be(Dur)Br] (CAAC = cyclic alkyl(amino)carbene, Dur = 2,3,5,6-tetramethylphenyl = duryl) with lithium sand in diethyl ether yields the first neutral, tricoordinate, and moderately stable beryllium radical, [(CAAC)(Et2O)BeDur]• (2-Et2O), which undergoes a facile second one-electron reduction concomitant with the insertion of the beryllium center into the endocyclic C-NCAAC bond and a cyclopropane-forming C-H bond activation of an adjacent methyl group. In situ generation of 2-Et2O and addition of PMe3 yield the stable analogue, [(CAAC)(Me3P)BeDur]• (2-PMe3), which serves as a platform for PMe3-ligand exchange with stronger donors, generating the radicals [(CAAC)LBeDur]• (2-L, L = isocyanides, pyridines, and N-heterocyclic carbenes). X-ray structural analyses show trigonal-planar beryllium centers and strong π backbonding from the metal to the CAAC ligand. The EPR signals of all six isolated [(CAAC)LBeDur]• radicals display significant, albeit small, hyperfine coupling to the 9Be nucleus. DFT calculations show that the spin density is mostly delocalized over the CAAC π framework and, where present, the isocyanide CN moiety, with only a small proportion (3-6%) on the beryllium center. 2-PMe3 proved thermally unstable at 80 °C, first undergoing radical hydrogen abstraction with the solvent, followed by insertion of beryllium into the endocyclic C-NCAAC bond and PMe3 transfer to the former carbene carbon atom. The reactions with diphenyl disulfide and phenyl azide occur at the beryllium center and yield the corresponding Be(II) phenyl sulfide and amino complexes, respectively, the latter concomitant with radical transfer and hydrogen abstraction by the beryllium-bound nitrogen center.