Methylation Of Compounds Research Articles

Catalytic undirected methylation of unactivated C(sp3)-H bonds suitable for complex molecules.

In pharmaceutical discovery, the "magic methyl" effect describes a substantial improvement in the pharmacological properties of a drug candidate with the incorporation of methyl groups. Therefore, to expedite the synthesis of methylated drug analogs, late-stage, undirected methylations of C(sp3)-H bonds in complex molecules would be valuable. However, current methods for site-selective methylations are limited to activated C(sp3)-H bonds. Here we describe a site-selective, undirected methylation of unactivated C(sp3)-H bonds, enabled by photochemically activated peroxides and a nickel(II) complex whose turnover is enhanced by an ancillary ligand. The methodology displays compatibility with a wide range of functional groups and a high selectivity for tertiary C-H bonds, making it suitable for the late-stage methylation of complex organic compounds that contain multiple alkyl C-H bonds, such as terpene natural products, peptides, and active pharmaceutical ingredients. Overall, this method provides a synthetic tool to explore the "magic methyl" effect in drug discovery.

Short communication: An alternative pathway for melatonin synthesis in the skin of European flounder (Platichthys flesus)

The classic melatonin biosynthesis pathway (Mel; N-acetyl-5-methoxytryptamine) involves two consecutive enzymatic steps that are decisive in hormone production: conversion of serotonin (5-hydroxytryptamine; 5-HT) to N-acetylserotonin (NAS) and the methylation of the last compound to Mel. This pathway requires the activity of the enzymes: the first is of the category of N-acetyltransferases (AANAT, SNAT, or NAT) and the second is N-acetylserotonin O-methyltransferase (ASMT; also known as HIOMT). However, quite recently, new information has been provided on the possibility of an alternative Mel synthesis pathway; it would include a two-step action by these enzymes, but in reverse order, where ASMT (or ASMTL, the enzyme related to ASMT) methylates 5-HT to 5-methoxytryptamine (5-MT), and then the last compound is acetylated by an enzyme of the category of N-acetyltransferases to Mel. In our study on the activity of enzymes in the Mel biosynthesis pathway in flounder skin, we have found an increase in 5-MT level, as a result of the increase in 5-HT concentration, which is followed by a growing concentration of Mel. However, we have not found any increase in Mel concentration, despite an increase in NAS in the samples. Our data strongly suggest an alternative way of Mel production in flounder skin in which 5-HT is first methylated to 5-MT, which is then acetylated to Mel.

Multicomponent Cross-Dehydrogenative Coupling of Imidazo[1,2-a]pyridine: Access to Abnormal Mannich and Mannich-Type Reaction.

This study showcases successfully switchable approaches to accomplish the C3-aryl methylation and C3- amino methylation of privileged nitrogen-containing pharmaceutical compounds "imidazopyridines" with distinct amines, which surmounts the long-standing requirement for a superfluous directing group. These two transformations manifest pronounced regio- and chemo-divergent behavior, successfully demonstrating unprecedented multicomponent "abnormal Mannich and Mannich-type" reactions. The remarkable environmentally benign protocol has been efficiently extended to concise the synthesis and late-stage derivatization.

A Novel O- and S-Methyltransferase from Pleurotus sapidus Is Involved in Flavor Formation.

Increasing consumer aversion to non-natural flavoring substances is prompting a heightened interest in enzymatic processes for flavor production. This includes methylation reactions, which are often performed by using hazardous chemicals. By correlation of aroma profile data and transcriptomic analysis, a novel O-methyltransferase (OMT) catalyzing a respective reaction within the formation of p-anisaldehyde was identified in the mushroom Pleurotus sapidus. Heterologous expression in E. coli followed by purification allowed for further characterization of the enzyme. Besides p-hydroxybenzaldehyde, the proposed precursor of p-anisaldehyde, the enzyme catalyzed the methylation of further hydroxylated aromatic compounds at the meta- and para-position. The Km values determined for p-hydroxybenzaldehyde and S-adenosyl-l-methionine were 80 and 107 μM, respectively. Surprisingly, the studied enzyme enabled the transmethylation of thiol-nucleophiles, as indicated by the formation of 2-methyl-3-(methylthio)furan from 2-methyl-3-furanthiol. Moreover, the enzyme was crystallized at a resolution of 2.0 Å, representing the first published crystal structure of a basidiomycetous OMT.

Controlled Ring Opening of a Tetracyclic Tetraphosphane with Twofold Metallocene Bridging.

A direct route to a doubly ferrocene bridged tetracyclic tetraphosphane 1 was developed via reductive coupling of Fe(CpPCl2)2 (2 a), where a chlorine terminated linear P4-compound 3 could be identified as an intermediate. Selective P-P bond activation was further achieved by reacting 1 with elemental selenium or [Cp*Al]4, where regioselective insertion of Se or Al atoms resulted in ferrocenylene bridged [P4Se] (4) or [P4Al] (7) moieties. Compound 7 can be transformed to a hydrogen terminated linear P4 species, 8, with protic solvents. Methylation of compound 1 with MeOTf, proceeds via intermediate formation of monomethylated species 5, which gradually produced Me2-terminated dicationic 6, again containing a linear P4-unit. Besides spectroscopic characterization, the structural details of compounds 1, 4, 6, and 8 could be determined by SC-XRD. Moreover, DFT calculations were used to rationalize the reactivity of 1, derived compounds and intermediates. As a key feature, 1 undergoes ring opening polymerization to a linear polyphosphane 9.

General and selective homogeneous Ru-catalyzed transfer hydrogenation, deuteration, and methylation of functional compounds using methanol

Catalytic valorization of methanol in organic synthesis and energy technologies is interesting and important for both fundamental research and industrial applications. In particular, its utilization as hydrogen, deuterium and methyl sources for selective reduction and deuteration reactions as well as to access N-methylated products is highly desirable and can be considered as a potential methodology for the amplification of transfer hydrogenation and C1 chemistry. Here, we report homogeneous Ru-MACHO complex catalyzed transfer hydrogenation of different functionalized compounds such as ketones, aldehydes, alkynes, alkenes, imines, azobenzenes, and nitro compounds as well as deoxygenation of N-oxide derivatives employing methanol as an affordable hydrogen donor and solvent. This Ru-based strategy has been proven to be very convenient for the deuteration process to synthesize advanced deuterium-labelled compounds, including the gram-scale synthesis of deuterated pharmaceuticals such as d-Cloperastine, d-Buclizine, d-Diphendyarmine, d-Modafinil, and d-Adrafinil using CD3OD. In addition, the application of methanol as a C1 source for the preparation of N-methylated products is showcased. Finally, kinetic and mechanistic investigations for this Ru-catalyzed transfer hydrogenation and deuteration protocols have been performed.

Monoselective N-Methylation of Amides, Indoles, and Related Structures Using Quaternary Ammonium Salts as Solid Methylating Agents.

We herein report the use of phenyl trimethylammonium iodide (PhMe3NI) as a safe, nontoxic, and easy-to-handle reagent for an absolutely monoselective N-methylation of amides and related compounds as well as for the N-methylation of indoles. In addition, we expanded the method to N-ethylation using PhEt3NI. The ease of operational setup, high yields of ≤99%, high functional group tolerance, and especially the excellent monoselectivity for amides make this method attractive for late-stage methylation of bioactive compounds.

Acidity effect on benzene methylation kinetics over substituted H-MeAlPO-5 catalysts

Methylation of aromatic compounds is a key reaction step in various industrial processes such as the aromatic cycle of methanol-to-hydrocarbons chemistry. The study of isolated methylation reactions and of the influence of catalyst acidity on their kinetics is a challenging task. Herein, we have studied unidirectional metal-substituted H-MeAlPO-5 materials to evaluate the effect of acid strength on the kinetics of benzene methylation with DME. First-principle simulations showed a direct correlation between the methylation barrier and acid site strength, which depends on the metal substituent. Three H-MeAlPO-5 catalysts with high (Me = Mg), moderate (Me = Si) and low acidity (Me = Zr) were experimentally tested, confirming a linear relationship between the methylation activation energy and acid strength. The effects of temperature and reactant partial pressure were evaluated, showing significant differences in the byproduct distribution between H-MgAlPO-5 and H-SAPO-5. Comparison with propene methylation suggested that the Mg substituted catalyst is also the most active for the selective methylation of alkenes.

Selenium (Se) as well as mercury (Hg) may influence the methylation and toxicity of inorganic arsenic, but further research is needed with combination of Inorg-arsenic, Se, and Hg

Selenium (Se) as well as mercury (Hg) may influence the methylation and toxicity of inorganic arsenic, but further research is needed with combination of Inorg-arsenic, Se, and Hg

Maternal methionine supplementation in mice affects long-term body weight and locomotor activity of adult female offspring.

Methionine is a precursor of s-adenosylmethionine, the main donor of methyl radicals for methylation of DNA and other compounds. Previous studies have shown that reduced availability of methyl radicals during pregnancy/lactation decreased offspring perigonadal white adipose tissue (PWAT) and body weight. Therefore, we aimed to evaluate the effects of methionine supplementation during early development, a time of great ontogenic plasticity, by assessing the biometric, biochemical and behavioural parameters of the offspring of adult Swiss female mice supplemented with 1 % methionine in water 1 month before pregnancy, during pregnancy or pregnancy/lactation. After birth, the offspring were distributed into three groups: control (CT), methionine supplementation during pregnancy (SP) and methionine supplementation during pregnancy and lactation (SPL), and were followed until postnatal day (PND) 300. No changes were observed in offspring birth weight in both sexes. At PND 5, 28 and 90, no differences in body weight were found in females; however, at PND 300, SP and SPL females showed an increase in body weight when compared with the control group. This increase in body weight was accompanied by a total and relative increase in PWAT, and a decrease in locomotor activity in these groups. No differences in the body and organ weights were found in male offspring. In conclusion, the increased availability of methyl radicals during pregnancy and lactation impacted long-term body composition and locomotor activity in female offspring.

Depletion of S-adenosylmethionine pool and promoter hypermethylation of Arsenite methyltransferase in arsenic-induced skin lesion individuals: A case-control study from West Bengal, India

Methylation of arsenic compounds in the human body occurs following a series of biochemical reactions in the presence of methyl donor S-adenosylmethionine (SAM) and catalyzed by arsenite methyltransferase (AS3MT). However, the extent and pattern of methylation differs among the arsenic exposed individuals leading to differential susceptibility. The mechanism for such inter-individual difference is enigmatic. In the present case-control study we recruited exposed individuals with and without arsenic induced skin lesion (WSL and WOSL), and an unexposed cohort, each having 120 individuals. Using ELISA, we observed a reduction in SAM levels (p < 0.05) in WSL compared to WOSL. Linear regression analysis revealed a negative correlation between urinary arsenic concentration and SAM concentration between the study groups. qRT-PCR revealed a significant down-regulation (p < 0.01) of key regulatory genes like MTHFR, MTR, MAT2A and MAT2B of SAM biogenesis pathway in WSL cohort. Methylation-specific PCR revealed significant promoter hypermethylation of AS3MT (WSL vs. WOSL: p < 0.01) which resulted in its subsequent transcriptional repression (WSL vs. WOSL: p < 0.001). Linear regression analysis also showed a negative correlation between SAM concentration and percentage of promoter methylation. Taken together, these results indicate that reduction in SAM biogenesis along with a higher utilization of SAM results in a decreased availability of methyl donor. These along with epigenetic down-regulation of AS3MT may be responsible for higher susceptibility in arsenic exposed individuals.

Скринінгове дослідження антиамнестичної активності нових похідних 4-амінобутанової кислоти

The purpose of the study is to conduct screening of newly synthesized derivatives of 4-aminobutanoic acid (BC) for the presence of antiamnestic activity and to identify the most active compounds that are promising for further study.The study included 11 new compounds ‒ derivatives of 4-aminobutanoic acid, which were synthesized at the National University of Pharmacy. The of the test compounds on mnestic functions was assessed in mice by the passive avoidance conditional reflex (PACR) test in a model of anterograde amnesia caused by scopolamine (1,5 mg/kg, intraperitoneally).As a result of pharmacological screening of 11 new derivatives of 4-aminobutanoic acid for the presence of antiamnestic activity, compounds were found that showed activity: KGM-2, KGM-5, KGM-6. Analysis of the «structure-antiamnestic effect» relationship for the synthesized series of compounds showed that the most active are 4-aminobutanoic acid derivatives containing a hydroxymethyl radical (KGM-1 and KGM-2). Introduction of methyl radical to the molecule KGM-2 leads to a decrease in antiamnestic activity (KGM-3). It was found that the replacement of one of the hydroxymethyl radicals in the molecule KGM-2 also helps to reduce the antiamnestic effect. Methylation of the basic compound (4-aminobutanoic acid, BC) contributed to the increase of activity only in cases when methyl and benzyl radicals (compounds KGM-5 and KGM-6) were present in the molecule. The introduction of methyl radicals only (compounds KGM-9; KGM-10 and KGM-11) enhances the antiamnestic activity compared to BC, and in the studied series of compounds they show high antiamnestic activity only at the highest dose of 50 mg / kg. It was found that the compounds KGM-1, KGM-2, KGM-5 show dose-dependent antiamnestic activity.Thus, among 11 derivatives of 4-aminobutanoic acid three compounds (KGM-2, KGM-5, KGM-6) with pronounced antiamnestic were selected as promising for further pharmacological study. The dependence of structure-antiamnestic effect has been proven: the introduction of hydroxymethyl radical enhances antiamnestic activity. The combination in the structure of both benzyl and methyl radicals provides a high antiamnestic effect.

Breast Cancer Disease and Arsenic: “Geological Behavior (GBR) as Key “

Geology may appear remote from human health. However, rocks are the fundamental building blocks of the Earth’s surface, full of important minerals and chemical elements. Rock weathering and alteration products not only form our soils to support our crops but provide essential elements to build biology. Some heavy metals are carcinogenic, and some only affect the body’s ability to produce red and white cells. In fact, any heavy metal affects any part of the body due to our geological behavior (GBR). For example, a heavy metal may not cause any side effects by contact with the skin, even when swallowed, and may not cause serious harm, but inhaling the vapor of that heavy, toxic metal can cause severe damage to the lungs. Some heavy and quasi metals are more toxic, and some forms of heavy metal compounds are even more dangerous than other forms. Toxic and hazardous heavy metals like arsenic, lead, mercury, zinc, chromium and iron are found in a variety of personal care products, e.g., lipstick, whitening toothpaste, eyeliner and nail color. We use the Anodic Stripping voltammetry (ASV) method for arsenic detection, utilizing the PDV6000 + analyzer (Manufactured B3 Electronics, Perth Australia) configured with a solid gold electrode for total as analyses. Sample Preparation: Spot urine samples were collected from most of the participants from 1 January 2018 to 30 March 2020 after face to face interviews. Women with missing information on adjustment variable(s) were included in the analysis in a separate category for adjustment. Results: Our studies were focus in describing the mean Urinary Arsenic levels (u As) residents of in the central zones of Shiraz, Fasa, Abadeh, Jahrom and Marvdasht to compare the effect of diet such as consuming canned or frozen foods, Consume rice daily, smoking habits and lifestyle on the incidence of Breast. Conclusion: Cancer with arsenic compounds has been reported in many parts of the world. The disease affects all organs of the body, and every year many victims of cancer suffer from severe symptoms and even death. Arsenic compounds are present in the human body and environment in an inorganic and organic form. Inorganic arsenic includes arsenite and arsenic, can also be presented in the environment in the form of methyl (monthly arsenic acid and dimethyl arsenic acid). Arsenic, especially inorganic arsenic, is well absorbed through the gastrointestinal tract rivers (80% -90%) and will be scattered throughout the body. It is often metabolized by methylation and excreted mainly in the urine. Methylation of inorganic arsenic compounds is said to undergo a detoxification process.

Comparative LC-MS analysis of tropolone alkaloids from in vitro cultures and native sources of Gloriosa superba by Kendrick mass defect plots.

Gloriosa superba L. is a promising antitumoural plant species as a source of colchicinoids. Ethnobotanical applications of G. superba are associated with different plant parts such as leaves, seeds, fruits, tuber and the whole plant. A comparative phytochemical study of purified extracts from in vitro cultures and native tubers of G. superba was carried out by ultrahigh-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HR-MS) in combination with the mass defect filtering (MDF) technique. The individual compounds were tentatively annotated using database correlations, retention time (Rt), accurate m/z data obtained by electrospray ionisation (ESI) (+)-HR-MS, proposed elemental composition, ring double bond equivalent (RDBeq) values and HR-MS/MS fragmentation patterns. Moreover, the identification was based on transforming the exact mass ratio (m/z) for the protonated molecular ions [М + Н]+ of the observed metabolites in Kendrick nominal masses (NKMs) and calculation of the Kendrick mass defect (KMD), which made it possible to graphically present the ion peaks in Kendrick plots. Building Kendrick plots allows easy differentiation of small structural differences such as methylation or demethylation of compounds from the same homologous series. In this way, a wide range of tropolone alkaloids was characterised. A greater variety was observed in in vitro cultures, compared to native sources. This LC-MS analysis unambiguously demonstrated the presence of tropolone alkaloids in in vitro cultures of G. superba. This approach of LC-MS data interpretation can be used to understand complex mass spectra such as those of plant extracts.

Palladium-Catalyzed Reductive Coupling of Aromatic Bromides and Trimethylsilyldiazomethane: Its Application to Methylation of Aromatic Compounds

Palladium-Catalyzed Reductive Coupling of Aromatic Bromides and Trimethylsilyldiazomethane: Its Application to Methylation of Aromatic Compounds

An Efficient Synthesis, Anti inflammatory activity and Molecular Docking Studies of new Triazinanes and Iminothiazolidinones

A series of new triazinane-2-thiones and imino thiazolidinone-4-ones were synthesized from 2-acetyl benzimidazole (1). Treatment of compound 1 with urea in the presence of I2 furnishes compound (2), which on reaction with Aryl isothiocyanateaffords the compound (3), which undergoes Cyclic condensation of classical Mannich amino methylation of compound 3with formaldehyde and methyl amine produces corresponding triazinane -2-thiones (4), whereas cyclic condensation of compound 3 with cholroacetic acid to furnish the corresponding iminothiazolidinones-4-ones(5).the chemical structures of the newly synthesized compounds have been characterized on the basis of spectral (IR, 1HNMR and Mass) and analytical data. The title compounds were evaluated for their anti-inflammatory activity and molecular docking studies. The docking studies are supporting anti-inflammatory activity exhibiting high inhibition constant and binding energy.

Chemical Degradation of Mercury Alkyls Mediated by Copper Selenide Nanosheets.

Methylation and demethylation of mercury compounds are two important competing processes that control the net production of highly toxic mercury alkyls, methylmercury (MeHg+ ) and dimethylmercury (Me2 Hg), in environment. Although the microbial and the photochemical methylation and demethylation processes are well studied in recent years but the chemical methylation and demethylation processes have not been studied well. Herein, we report for the first time that the CuSe nanosheet has remarkable ability to activate the highly inert Hg-C bonds of various MeHg+ and Me2 Hg compounds at room temperature (21 °C). It facilitates the conversion of MeHg+ into Me2 Hg in the absence of any proton donors. Whereas, in the presence of any proton source, it has unique ability to degrade MeHg+ into CH4 and inorganic mercury (Hg2+ ). Detailed studies revealed that the relatively fast Hg-C bond cleavage was observed in case of MeHgSPh or MeHgI in comparison to MeHgCl, indicating that the Hg-C bond in MeHgCl is relatively inert in nature. On the other hand, the Hg-C bond in Me2 Hg is considered to be exceedingly inert and, thus, difficult to cleave at room temperature. However, CuSe nanosheets showed unique ability to degrade Me2 Hg into CH4 and Hg2+ , via the formation of MeHg+ , under acidic conditions at room temperature. DFT calculations revealed that the Hg-C bond activation occurs through adsorption on the surface of (100)-faceted CuSe nanosheets.

SAHH and SAMS form a methyl donor complex with CCoAOMT7 for methylation of phenolic compounds

A wealth of studies illustrate the powerful antioxidant activities and health-promoting functions of dietary phenolic compounds, e.g., anthocyanins, flavonoids, and phenolic compounds. Ferulate is methylated from caffeoyl CoA using S-adenosyl-L-methionine (SAM) as methyl donor catalyzed by caffeoyl CoA methyltransferase (CCoAOMT). Here we show that Arabidopsis CCoAOMT7 contributes to ferulate content in the stem cell wall. CCoAOMT7 was further shown to bind S-adenosyl-L-homocysteine hydrolase (SAHH), a critical step in SAM synthesis to release feedback suppression on CCoAOMT. CCoAOMT7 also bound S-adenosyl-L-methionine synthases (SAMSs) in vivo, which were mediated by SAHH1. Interruptions of endogenous SAHH1 by artificial miRNA or SAMSs by T-DNA insertion significantly reduced ferulate contents in the stem cell wall. This data reveals a novel protein complex of SAM synthesis cycle associated with O-methyltransferase and provides new insights into cellular methylation processes.

A Parasitic Arsenic Cycle That Shuttles Energy from Phytoplankton to Heterotrophic Bacterioplankton.

In many regions of the world oceans, phytoplankton face the problem of discriminating between phosphate, an essential nutrient, and arsenate, a toxic analogue. Many phytoplankton, including the most abundant phytoplankton group known, Prochlorococcus, detoxify arsenate (AsV) by reduction to arsenite (AsIII), followed by methylation and excretion of the methylated arsenic products. We synthesized [14C]dimethyl arsenate (DMA) and used it to show that cultured Pelagibacter strain HTCC7211 (SAR11) cells oxidize the methyl group carbons of DMA, producing 14CO2 and ATP. We measured [14C]DMA oxidation rates in the P-depleted surface waters of the Sargasso Sea, a subtropical ocean gyre. [14C]DMA was oxidized to 14CO2 by Sargasso Sea plankton communities at a rate that would cause turnover of the estimated DMA standing stock every 8.1 days. SAR11 strain HTCC7211, which was isolated from the Sargasso Sea, has a pair of arsenate resistance genes and was resistant to arsenate, showing no growth inhibition at As/P ratios of >65:1. Across the global oceans, there was a strong inverse relationship between the frequency of the arsenate reductase (LMWPc_ArsC) in Pelagibacter genomes and phosphate concentrations. We propose that the demethylation of methylated arsenic compounds by Pelagibacter and possibly other bacterioplankton, coupled with arsenate resistance, results in the transfer of energy from phytoplankton to bacteria. We dub this a parasitic cycle because the release of arsenate by Pelagibacter in principle creates a positive-feedback loop that forces phytoplankton to continually regenerate arsenate detoxification products, producing a flow of energy to P-limited ocean regions.IMPORTANCE In vast, warm regions of the oceans, phytoplankton face the problem of arsenic poisoning. Arsenate is toxic because it is chemically similar to phosphate, a scarce nutrient that phytoplankton cells need for growth. Many phytoplankton, including the commonest phytoplankton type in warm oceans, Prochlorococcus, detoxify arsenate by adding methyl groups. Here we show that the most abundant non-photosynthetic plankton in the oceans, SAR11 bacteria, remove the methyl groups, releasing poisonous forms of arsenic back into the water. We postulate that the methylation and demethylation of arsenic compounds creates a cycle in which the phytoplankton can never get ahead and must continually transfer energy to the SAR11 bacteria. We dub this a parasitic process and suggest that it might help explain why SAR11 bacteria are so successful, surpassing all other plankton in their numbers. Field experiments were done in the Sargasso Sea, a subtropical ocean gyre that is sometimes called an ocean desert because, throughout much of the year, there is not enough phosphorous in the water to support large blooms of phytoplankton. Ocean deserts are expanding as the oceans absorb heat and grow warmer.

Biomass-derived N-doped porous carbon: an efficient metal-free catalyst for methylation of amines with CO2

Developing metal-free heterogeneous catalysts for methylation of N–H with CO2 is highly desired. Our work demonstrates the feasibility of using N-doped porous carbons (NPCs) to catalyze the methylation of amino compounds with CO2 for the first time.