Methylation Reactions Research Articles

Solvent-Free Synthesis, In Vitro and In Silico Studies of Novel Potential 1,3,4-Thiadiazole-Based Molecules against Microbial Pathogens.

A new series of 1,3,4-thiadiazoles was synthesized by the reaction of methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate (2) with selected derivatives of hydrazonoyl halide by grinding method at room temperature. The chemical structures of the newly synthesized derivatives were resolved from correct spectral and microanalytical data. Moreover, all synthesized compounds were screened for their antimicrobial activities using Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Bacillus subtilis, Staphylococcus aureus, and Candida albicans. However, compounds 3 and 5 showed significant antimicrobial activity against all tested microorganisms. The other prepared compounds exhibited either only antimicrobial activity against Gram-positive bacteria like compounds 4 and 6, or only antifungal activity like compound 7. A molecular docking study of the compounds was performed against two important microbial enzymes: tyrosyl-tRNA synthetase (TyrRS) and N-myristoyl transferase (Nmt). The tested compounds showed variety in binding poses and interactions. However, compound 3 showed the best interactions in terms of number of hydrogen bonds, and the lowest affinity binding energy (−8.4 and −9.1 kcal/mol, respectively). From the in vitro and in silico studies, compound 3 is a good candidate for the next steps of the drug development process as an antimicrobial drug.

Selective nanosensor based on folic acid imprinted nanostructures.

Folic acid, which provides the transfer of single carbon atoms in synthesis reactions and metabolic cycles in metabolism, is very important for metabolism. Folic acid also plays an important role in nucleotide synthesis and methylation reactions. There are many disorders caused by defective folic acid metabolism and lack of folic acid. Today, innovative, cost-effective methods are needed to develop folic acid determination methods. The main objective of this study is the development of surface-printed carbon electrodes (SPCE) modified with folic acid imprinted nanostructures (FA-Imp-poly(MPTS-rGO-co-NAT), which will be used for the first time for folic acid determination in commercially human blood serum. For this purpose, the synthesis of nanostructures has been carried out and characterized by FTIR, SEM-EDS, and AFM. Then, a new chemically modified nanosensor was fabricated for the determination of folic acid using folic acid imprinted nanostructures. Differential pulse voltammetry (DPV) and circular voltammetry (CV) methods were used as electrochemical methods in the FA-imprinted-nanosensor studies. Measurements in differential pulse voltammetry were performed at an application speed of 0.005 volts per second in the potential range of -0.4 to 0.6 volts. As a result of the circular voltammetric method, an idea about the surface was obtained with the voltammograms obtained. The detection limit (LOD) of the developed FA-imprinted-nanosensor was 7.54 ng/mL and the determination limit (LOQ) was 25.14 ng/mL. FA analytical (10 and 20 ng/mL) was added to commercial synthetic serum samples by the standard adding method and RSD values of 0.092% and 0.734% were found in the DPV technique and measurements respectively. This manuscript demonstrated a novel, simple, selective, and rapid FA-imprinted-nanosensor for determining the FA in the biological samples.

Behavioral profile of vitamin B12 deficiency: A reflection of impaired brain development, neuronal stress and altered neuroplasticity.

Our understanding of brain biology and function is one of the least characterized and therefore, there are no effective treatments for most of neurological disorders. The influence of vitamins, and particularly vitamin B12, in neurodegenerative disease is demonstrated but largely unresolved. Behaviors are often quantified to attest brain dysfunction alone or in parallel with neuro-imaging to identify regions involved. Nevertheless, attention should be paid to extending observations made in animal models to humans, since, first, behavioral tests have to be adjusted in each model to address the initial question and second, because brain analysis should not be conducted for a whole organ but rather to specific sub-structures to better define function. Indeed, cognitive functions such as psychiatric disorders and learning and memory are often cited as the most impacted by a vitamin B12 deficiency. In addition, differential dysfunctions and mechanisms could be defined according sub-populations and ages. Vitamin B12 enters the cell bound to Transcobalamin, through the Transcobalamin Receptor and serves in two cell compartments, the lipid metabolism in the mitochondrion and the one-carbon metabolism involved in methylation reactions. Dysfunctions in these mechanisms can lead to two majors outcomes; axons demyelinisation and upregulation of cellular stress involving mislocalization of RNA binding proteins such as the ELAVL1/HuR or the dysregulation of pro- or anti-oxidant NUDT15, TXNRD1, VPO1 and ROC genes. Finally, it appears that apart from developmental problems that have to be identified and treated as early as possible, other therapeutic approaches for behavioral dysfunctions should investigate cellular methylation, oxidative and endoplasmic reticulum stress and mitochondrial function.

Spectrophotometric method development for thiophante methyl based systemic fungicide, Roko formulation

The thiophanate methyl globally used to control most commonfungal diseasesin crops and usually metabolized in animals intobenzimidazolecompounds, including the reproductive toxicantcarbendazim. Therefore there is dire need to monitor the thiophanate methyl level in formulations and residues for quality control purpose and in environment samples respectively. The current spectrophotometric investigation has been based on reaction characteristics of the thiourea functionality to develop the color reaction (λmax at 368 nm) of thiophanate methyl with cobalt acetate in the presence of pyridine to devise the rugged and sensitive method for the estimation of thiophante methyl in Roko formulation (70 % WP, thiophanate methyl). The optimized color reaction at λmax at 368 nm has been explored due to its excellent stability(3 h), sensitivity (ε: 5.45 × 103 LM−1 cm−1) and wider linearity range upto 56 μgmL−1 in DMF solvent. The current methodology has been successfully applied to estimation of active ingredient in Roko formulation for the quality control purpose. Present works is simple and cost effective for the purpose of quality check to regulate the entry of adulterated and sub standard formulation into agrochemical market before its application to agricultural field.

Electrochemical synthesis of dipyrazolo/dipyrimidine-fused pyridines via oxidative domino cyclization of C(sp3)–H bonds

An electrochemically oxidative domino cyclization reaction of methyl azaarenes/ketones with pyrazol-5-amines and 6-amino-pyrimidine-2,4-diones was developed, providing a variety of dipyrazolo/dipyrimidine-fused pyridines with moderate to good yields.

Analogs of S-Adenosyl-L-Methionine in Studies of Methyltransferases

Methyltransferases (MTases) play an important role in the functioning of living systems, catalyzing the methylation reactions of DNA, RNA, proteins, and small molecules, including endogenous compounds and drugs. Many human diseases are associated with disturbances in the functioning of these enzymes; therefore, the study of MTases is an urgent and important task. Most MTases use the cofactor S-adenosyl-L-methionine (SAM) as a methyl group donor. SAM analogs are widely applicable in the study of MTases: they are used in studies of the catalytic activity of these enzymes, in identification of substrates of new MTases, and for modification of the substrates or substrate linking to MTases. In this review, new synthetic analogs of SAM and the problems that can be solved with their usage are discussed.

Modulating the reactivity of polymer with pendant ester groups by methylation reaction for preparing functional polymers

Chemical reaction triggered the reactivity of polymeric esters.

Charge transfer complex enabled photoreduction of Wittig phosphonium salts

An efficient photoactive charge transfer complex protocol for the (alkoxycarbonyl)methylation reaction of alkenes with phosphonium salts is established.

Understanding the acrylates formation from CO2 and ethylene over Ni- and Pd-based catalysts: A DFT study on the effects of solvents, methyl halides, and ligands

In this work, two methylation reaction pathways were investigated to explore the role of solvent and I− on the formation of methyl acrylate from coupling of CO2 and ethylene catalyzed by nickel and palladium catalysts in the presence of MeI. The stabilization of non-productive intermediates is inhibited in the gas phase as well as in low-polar solvents, which explains the requirement of high excess of MeI to obtain high yields of methyl acrylate. The energy barrier for M-O bond cleavage as well as the stability of the overall reaction intermediates is consistent with the corresponding halogen electron-donating ability. The different catalytic behaviors of various bidentate ligands on Ni- and Pd-based catalysts were systematically investigated, mainly including dmpe(1,2-bis(dimethylphosphino)ethane), tmeda(tetramethylethylenediamine), dppe(1,2-bis(diphenylphosphino)ethane), dcpe(1,2-bis(dicyclohexylphosphino)ethane) and dtbpe(1,2-bis(di-tert-butylphosphino)ethane). The energy barrier of M-O bond cleavage increases with the enhancement of ligand steric hindrance in the O1 (ester sp3 O atom) attack mechanism, while the corresponding O2 (carboxylic sp2 O atom) attack mechanism shows an opposite trend. The energy barrier of β-H elimination in both catalytic systems is strongly related to the electron-donating ability of the diphosphine ligand substituents. The dcpp(1,3-bis(dicyclohexylphosphino)propane) ligand shows relatively good performance for β-H elimination among all the investigated ligands in Pd-mediated system. In general, diphosphine ligands are superior to diamine ligands in Pd-mediated system in terms of efficiency.

Global genomic analysis of microbial biotransformation of arsenic highlights the importance of arsenic methylation in environmental and human microbiomes

Arsenic is a ubiquitous toxic element, the global cycle of which is highly affected by microbial redox reactions and assimilation into organoarsenic compounds through sequential methylation reactions. While microbial biotransformation of arsenic has been studied for decades, the past years have seen the discovery of multiple new genes related to arsenic metabolism. Still, most studies focus on a small set of key genes or a small set of cultured microorganisms. Here, we leveraged the recently greatly expanded availability of microbial genomes of diverse organisms from lineages lacking cultivated representatives, including those reconstructed from metagenomes, to investigate genetic repertoires of taxonomic and environmental controls on arsenic metabolic capacities. Based on the collection of arsenic-related genes, we identified thirteen distinct metabolic guilds, four of which combine the aio and ars operons. We found that the best studied phyla have very different combinations of capacities than less well-studied phyla, including phyla lacking isolated representatives. We identified a distinct arsenic gene signature in the microbiomes of humans exposed or likely exposed to drinking water contaminated by arsenic and that arsenic methylation is important in soil and in human microbiomes. Thus, the microbiomes of humans exposed to arsenic have the potential to exacerbate arsenic toxicity. Finally, we show that machine learning can predict bacterial arsenic metabolism capacities based on their taxonomy and the environment from which they were sampled.

Quantitation of 5-Methyltetrahydrofolate in Cerebrospinal Fluid Using Liquid Chromatography-Electrospray-Tandem Mass Spectrometry.

We describe a simple stable isotope dilution method for accurate and precise measurement of cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5-MTHF) as a clinical diagnostic test. 5-MTHF is the main biologically active form of folate and is involved in the regulation of homocysteine and numerous methylation reactions, including synthesis of neurotransmitters, lipids, DNA, and RNA. Measurement of 5-MTHF in CSF provides diagnostic information regarding disorders affecting folate metabolism within the central nervous system, in particular inborn errors of folate metabolism and cerebral folate deficiency. Determination of 5-MTHF in CSF (50μL) was performed utilizing high-performance liquid chromatography coupled with electrospray positive ionization tandem mass spectrometry (HPLC-ESI-MS/MS). 5-MTHF in CSF is determined by a 1:2 dilution with internal standard (5-MTHF-13C5) and injected directly onto the HPLC-ESI-MS/MS system. Each assay is quantified using a five-point standard curve (25-400nM) and has an analytical measurement range of 3-1000nM.

Role of Folate and Folic Acid During Pregnancy

Abstract: Pregnancy represents a period of fast tissue growth of maternal and foetal tissues that's related to enhanced energy and nutrient needs. Maternal nutrition throughout gestation period, has being essential for best offspring development, reducing long unwellness burden and for general health throughout life. Maternal Folate throughout pregnancy might have numerous roles in offspring health, as well as neurodevelopment and psychological feature performance in childhood. Folate is crucial for C1 metabolism, a network of pathways concerned in many biological processes as well as nucleotide synthesis, deoxyribonucleic acid repair and methylation reactions. The periconceptional use of pteroylglutamic acid (Folic Acid ) containing supplements reduces the primary incidence, as well as recurrence of neural tube defects. Folic Acid (FA) are artificial form of a necessary vitamin generically considered Folates or B9. It is concerned in one-carbon metabolism, and it's been connected to lowering neural tube Defect (NTD). National programs to mandate fortification of food with Folic Acid have reduced the prevalence of NTDs worldwide . The indisputable protecting role of Folic Acid in the hindrance of NTD, in addition to the low compliance of women to Folic Acid recommendations, has aroused the choice of mandatory Folic Acid fortification, a policy currently in place in over eighty countries worldwide. Mandatory food fortification needs food makers to feature Folic Acid to certain foods (e.g. starch or grain products), whereas voluntary fortification permits Folic Acid to be added to foods at the discretion of manufacturers. Food fortification with Folic Acid because the intervention is likely to achieve increasing Folic Acid intake among populations throughout the world. The objective of this article is to discuss the Role of Folic Acid and Folate during pregnancy and to review the role of Folate and Folic Acid , metabolism , absorption and Folic Acid effects on maternal on the basis of recent findings that are important for implementation of fortified food to design future studies. Keywords: Neurodevelopment, Methylation Reactions, Pteroylglutamic Acid, Bioavailability, Monoglutamates.

Reactions of methyl, hydroxyl and peroxyl radicals with the DOTA chelating agent used in medical imaging

The mechanism of reaction of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) with ·CH3, CH3O2· and ·OH radicals were studied. The radicals were formed in situ radiolytically. The methyl radicals react orders of magnitude slower with DOTA and with MIII(DOTA)- than the hydroxyl radicals. The various final products were identified and mechanisms for their formation are proposed. CH3O2· radicals do not react, or react too slowly to be observed, with DOTA and with MIII(DOTA)- as long as the central cation is not oxidized by the peroxyl radical. The results imply that synthesis of the MIII(DOTA)-(MIII = radioisotope) complexes in a water-organic solvent (ethanol or 2-propanol or acetonitrile) mixture is not only kinetically desired but the so formed complex also decreases the radiolytic decomposition of DOTA.

Effects of Glycine Supplementation on Mitochondrial Function and Protein Degradation in Skeletal Muscle of Old Mice

Glycine is the simplest amino acid and it has a pivotal role in different metabolic processes, such as being a building block of glutathione, collagen and purine bases, or taking part in methylation reactions, detoxication and ammonia metabolism. Although considered for many years a non-essential amino acid, glycine levels are decreased in certain conditions, as the endogenous synthesis cannot fulfill the needs required to sustain all the cellular processes in which glycine is involved. Here we describe that glycine levels are significantly lower in skeletal muscle of aged zebrafish and mice and in plasma of humans compared to young subjects. We therefore fed healthy old mice for 6 weeks with a glycine-supplemented diet and observed a significant restoration of glycine levels in skeletal muscle and liver towards young mouse levels. Moreover, old mice showed decreased mitochondrial function in glycolytic and oxidative fibers, and a significant increase in oxygen consumption was observed in glycolytic fibers after glycine supplementation. The improvement of mitochondrial function is not associated to an increased mitochondrial biogenesis or an increased antioxidant capacity, but glycine supplementation increases both total GSH and GSSG levels, suggestive of a pro-oxidant environment. Overall, glycine supplementation induced an increase in the cross-sectional area of fibers. Finally, we carried out RNA-Seq study to decipher the impact of higher glycine intake. Our results suggest that age-associated glycine deficiency plays an important role in atrophy of muscle, especially in glycolytic fibers, and is reversible with a dietary supplementation.

One-pot synthesis of heteroaromatic acetals via selectfluor-mediated tandem reaction of methyl quinoline-2-carboxylate and methanol

Here we report a mild Ag-catalyzed domino acetalization reaction using quinoline-2-carboxylates, which were substructures in a number of natural products. Methanol was directly utilized as the source of the acetal part. The main features of the domino reaction include the Minisci reaction, oxidation, and acetalization. Hydrogen fluoride generated in-situ participates in the Minisci reaction, and no external acids were needed. This domino reaction provides a simple and versatile route to heteroaromatic acetals under mild condition with good functional group tolerance using methanol.

Direct Detection of the Photorearrangement Reaction of Quinoline-Protected Dialkylanilines.

ABSTRACTThe photolysis reactions of (8‐cyano‐7‐hydroxyquinolin‐2‐yl)methyl (CyHQ)‐caged amines have been investigated using time‐resolved spectroscopy methods. Unexpectedly, an unconventional Hofmann‐Martius rearrangement reaction with high yield and regioselectivity occurred during the photolysis of some CyHQ‐protected dialkylanilines (such as compounds 1a and 2a). To have more insights into the mechanism of this unexpected photorearrangement reaction, we characterized the reaction intermediates directly using time‐resolved spectroscopy. Our new results showed that the anionic form of compound 1a was photoexcited to the singlet excited state, then a heterolytic cleavage of the C‐N bond took place to give CyHQ+ and the corresponding aniline. Thereafter, the recombined intermediate 6 was found to appear in about 19.7 and 44.3 ps for 1a (A) and 2a (A), respectively, before the generation of an ortho‐substituted aniline (1b and 2b) via the excited‐state deprotonation of 6. Thus, a logical photodynamic mechanism of this photoinduced Hofmann‐Martius rearrangement reaction was deduced. This new insight into the reaction mechanisms may be helpful for the design of novel related photoactivatable aniline molecules and for understanding other similar photorearrangement reaction mechanisms.

Theoretical studies of the reactions of methyl radical with dimethyl ether and 1,2-ethanediol

The CH3OCH3 + CH3 and (CH2OH)2 + CH3 reactions were characterized using CCSD(T)/CBS//M06-2x/cc-pVTZ theory. For the two reactions, a total of five reaction channels have been described, including the H-abstraction channels. The rate coefficients were calculated by CVT/SCT and the fitting parameters of Arrhensive formulas were given. The calculated rate coefficients agreed well with the available reference values. Note that the H-abstraction channel is the dominant channel over almost the calculated temperature range for the CH3OCH3 + CH3 reaction. The H-abstraction from CH2 group is predominant less than 1100 K and the the H-abstraction from the OH group become important higher than 1200 K in the (CH2OH)2 + CH3 reaction.

Investigation and Analytical Applications of the Reaction of N1-methylnicotinamide and Active Methylene Containing Drugs

Background: The reaction between N1-methylnicotinamide iodide (NMNI) and the active methylene group-containing compounds yields a fluorescent product, which can be used in the quantitative determination of certain drugs. Objective: The objective is to develop, adapt, and validate a simple spectrofluorometric method for the quantitative analysis of modafinil 1, budesonide 2, allicin 3, and florfenicol 4. Methods: Spectral analysis (elemental analysis, 1H, 13C NMR, MS), computational methods (geometry optimization, Gibbs free energy and pKa calculations) and spectrofluorometric approaches were conducted. Results: A C4 cyclization pathway was confirmed for the formation of the fluorophore. The spectrofluorometric method showed good linearity (R2= 0.996-0.999) over concentrations of 1-50 ng/mL, 0.5-5 ng/mL, 60-150 pg/mL, and 1-15 ng/mL of the standard solutions of 1, 2, 3, and 4, respectively. Conclusion: The proposed method is simple and suitable for quality control and assurance studies

Structural and Molecular Basis of the Catalytic Mechanism of Geranyl Pyrophosphate C6‐Methyltransferase: Creation of an Unprecedented Farnesyl Pyrophosphate C6‐Methyltransferase

AbstractPrenyl pyrophosphate methyltransferases enhance the structural diversity of terpenoids. However, the molecular basis of their catalytic mechanisms is poorly understood. In this study, using multiple strategies, we characterized a geranyl pyrophosphate (GPP) C6‐methyltransferase, BezA. Biochemical analysis revealed that BezA requires Mg2+ and solely methylates GPP. The crystal structures of BezA and its complex with S‐adenosyl homocysteine were solved at 2.10 and 2.56 Å, respectively. Further analyses using site‐directed mutagenesis, molecular docking, molecular dynamics simulations, and quantum mechanics/molecular mechanics calculations revealed the molecular basis of the methylation reaction. Importantly, the function of E170 as a catalytic base to complete the methylation reaction was established. We also succeeded in switching the substrate specificity by introducing a W210A substitution, resulting in an unprecedented farnesyl pyrophosphate C6‐methyltransferase.

Structural and Molecular Basis of the Catalytic Mechanism of Geranyl Pyrophosphate C6-Methyltransferase: Creation of an Unprecedented Farnesyl Pyrophosphate C6-Methyltransferase.

Prenyl pyrophosphate methyltransferases enhance the structural diversity of terpenoids. However, the molecular basis of their catalytic mechanisms is poorly understood. In this study, using multiple strategies, we characterized a geranyl pyrophosphate (GPP) C6-methyltransferase, BezA. Biochemical analysis revealed that BezA requires Mg2+ and solely methylates GPP. The crystal structures of BezA and its complex with S-adenosyl homocysteine were solved at 2.10 and 2.56 Å, respectively. Further analyses using site-directed mutagenesis, molecular docking, molecular dynamics simulations, and quantum mechanics/molecular mechanics calculations revealed the molecular basis of the methylation reaction. Importantly, the function of E170 as a catalytic base to complete the methylation reaction was established. We also succeeded in switching the substrate specificity by introducing a W210A substitution, resulting in an unprecedented farnesyl pyrophosphate C6-methyltransferase.