Methylation Reactions Research Articles

Universal Reagent for Mild and Stereospecific Nucleophilic Substitution of Alcohols with Amines.

A user-friendly reagent for mild and general activation of alcohols towards bimolecular nucleophilic substitution (SN2) leveraging diverse nucleophiles, including primary and secondary amines is reported herein. The new ion-paired reagent discovery was based upon the putative zwitterionic betaine intermediate of the Mitsunobu reaction and enabled the one-step conversion of enantioenriched alcohols to valuable chiral C-X bonds (where X = N, C, S, O or halide). The described activating reagent has also been applied to a one-step methylation reaction using methanol and to an intermolecular amination/intramolecular cyclization sequence that generates heterocycles, such as tetrahydroisoquinolines. This work provides the first evidence by X-ray crystallography of a protonated betaine as intermediate in the Mitsunobu reaction.

Exploring the Adsorption and Reactions of Methyl Radicals on M(111) Surfaces (M = Cu, Ag, Au): A DFT Study.

It was reported that adsorbed methyl radicals produce ethane with Ag0- and Au0-nanoparticles in aqueous media, whereas on Cu0-powders, the product is methanol. The source of these differences was explored computationally, using the DFT method. The results indicate that up to six radicals can be adsorbed on Ag(111) and Au(111), (top site), while only four can be adsorbed on Cu(111) (fcc site), each surface containing eight atoms. The diffusion of the radicals on the surface is very easy on silver and copper, as this is achieved with a very low barrier (0.06 eV and 0.15 eV for Ag(111) and Cu(111), respectively), while on Au(111), the barrier is higher, 0.51 eV. The formation of ethane via a reaction of two adsorbed radicals is thermodynamically plausible for all studied coverage ratios on the three surfaces, but kinetically, it is plausible at room temperature only on Au(111) and Ag(111) at full coverage. Ethane can also be produced on Au(111) and Ag(111) by a collision of a solvated radical and an adsorbed radical. This is a barrierless process. On Cu(111), the yield of such a process is CH4(aq), and an adsorbed CH2 which reacts further with a non-adsorbed water molecule to produce adsorbed CH3OH.

Genetic improvement of low-lignin poplars: a new strategy based on molecular recognition, chemical reactions and empirical breeding.

As an important source of pollution in the papermaking process, the presence of lignin in poplar can seriously affect the quality and process of pulping. During lignin synthesis, Caffeoyl-CoA-O methyltransferase (CCoAOMT), as a specialized catalytic transferase, can effectively regulate the methylation of caffeoyl-coenzyme A (CCoA) to feruloyl-coenzyme A. Targeting CCoAOMT, this study investigated the substrate recognition mechanism and the possible reaction mechanism, the key residues of lignin binding were mutated and the lignin content was validated by deep convolutional neural-network model based on genome-wide prediction (DCNGP). The molecular mechanics results indicate that the binding of S-adenosyl methionine (SAM) and CCoA is sequential, with SAM first binding and inducing inward constriction of the CCoAOMT; then CCoA binds to the pocket, and this process closes the outer channel, preventing contamination by impurities and ensuring that the reaction proceeds. Next, the key residues in the recognition process of SAM (F69 and D91) and CCoA (I40, N170, Y188 and D218) were analyzed, and we identified that K146 as a base catalyst is important for inducing the methylation reaction. Immediately after that, the possible methylation reaction mechanism was deduced by the combination of Restrained Electrostatic Potential (RESP) and Independent Gradient Model (IGM) analysis, focusing on the catalytic center electron cloud density and RESP charge distribution. Finally, the DCNGP results verified that the designed mutant groups were all able to effectively reduce the lignin content and increase the S-lignin content/ G-lignin content ratio, which was beneficial for the subsequent lignin removal. Multifaceted consideration of factors that reduce lignin content and combined deep learning to screen for favorable mutations in target traits provides new ideas for targeted breeding of low-lignin poplars.

Folinic acid as a treatment for autism in children: A within-subjects open-label study on safety and efficacy.

The folate cycle has been implicated in the pathophysiology of autism due to its role in the glutathione oxidative stress pathway, amino acid and DNA methylation reactions, and neurotransmitter synthesis pathway. Previous research on folinic acid supplementation in autistic children has suggested potential benefits. The primary aim of this pilot study was to determine the safety, feasibility and efficacy of oral folinic acid in improving communication and behaviour in autistic children. Ten autistic children were recruited into an open-label pre-post treatment within-subjects design study. At T = 0, 12 and 24 weeks, participants underwent safety evaluations, standardized assessments of language, autism symptoms, adaptive skills and global illness severity, and eye-gaze tracking. During the control period (0-12 weeks), participants continued with standard care. In the treatment period (12-24 weeks), participants took oral folinic acid at 2mg/kg/day. All 10 children (nine boys, one girl; aged 4-8years), successfully consumed oral folinic acid supplements with no adverse events. There was a reduction in Pervasive Developmental Disorder Behavior Inventory (PDDBI) Autism Composite T-score with treatment (mean [SD] T-score 49.2 [8.89] pre-treatment, 44.6 [6.19] post-treatment, p = 0.103). Although this difference was not statistically significant due to the small sample size, the effect size was medium-large, indicating that, as a group, there were clinically meaningful changes in PDDBI T-scores. There were also trends towards gains in communication scores and overall Clinical Global Impression scores. Folinic acid is a safe and feasible potential treatment for autism, and results from this pilot justify the need for a larger placebo-controlled trial.

Selective Borylation of C(sp3)−H Bond of Methyl Ethers Catalyzed by Iron Complexes Bearing Anionic Benzene‐Based PCP‐Pincer Ligands

AbstractHighly selective catalytic C(sp3)−H borylation of methoxy groups has been achieved using newly synthesized iron complexes bearing benzene‐based PCP‐type pincer ligands as catalysts. Reactions of various aryl and alkyl methyl ethers as substrates with bis(pinacolato)diboron under mild reaction conditions proceeded to afford the corresponding methoxy borylated products in good to high yields. A successful example of the iron‐catalyzed C(sp3)−H borylation of a methylene group of tetrahydrofuran (THF) was also presented. A plausible reaction pathway is proposed based on the experimental result of some stoichiometric reactions and DFT calculations on a model reaction, where iron‐boryl and ‐alkyl complexes may work as key intermediates.

Single-Molecule Nanopore Sequencing of the CpG Island from the Promoter of O6-Methylguanine-DNA Methyltransferase Provides Insights into the Mechanism of De Novo Methylation of G/C-Rich Regions

Background: The methylation of cytosine residues at CpG sites within the O6-methylguanine-DNA methyltransferase (MGMT) promoter is a key biomarker in glioblastoma therapy. The MGMT promoter (MGMTp) contains multiple guanine-rich sequences capable of folding into G-quadruplexes (G4s), but their relevance for MGMTp methylation is poorly understood. Objectives: Our study explores the impact of potential G-quadruplex-forming sequences (PQS) in the MGMT promoter CpG island on the activity of de novo DNA methyltransferase Dnmt3a. Additionally, we investigate their influence on the accuracy of methylation pattern detection using nanopore sequencing. Methods: Nanopore sequencing was employed to analyze the methylation of 94 clinically significant CpG sites in the human MGMTp using an in vitro de novo methylation system. Circular dichroism spectroscopy was used to identify G4 structures within the MGMTp CpG island. Interactions between the catalytic domain of Dnmt3a and the PQS from the MGMTp were examined by biolayer interferometry. Results: Guanine-rich DNA strands of the PQSs in the MGMTp were hypomethylated, while the complementary cytosine-rich strands were methylated by DNA methyltransferase Dnmt3a with higher efficiency. The accuracy of detecting modified bases in the PQS was significantly lower compared to surrounding sequences. Single-stranded guanine-rich DNA sequences from the MGMTp exhibited strong binding to Dnmt3a-CD, with an affinity approximately 10 times higher than their cytosine-rich complements (Kd = 3 × 10−8 M and 3 × 10−7 M, respectively). By binding to Dnmt3a, G4-forming oligonucleotides from MGMTp effectively inhibited the methylation reaction (IC50 6·10−7 M). Conclusions: The obtained data indicate the role of PQSs in establishing de novo methylation of the MGMT promoter. They also highlight the challenges of sequencing guanine-rich regions and the impact of specific de novo methylation patterns on clinical data interpretation.

A linear approach for the total synthesis of sex pheromone (3S, 5R, 6S)-6-isopropyl-3,5-dimethyltetrahydro-2H-pyran-2-one and prelactone B

A linear 10-step approach for the stereoselective total synthesis of (3S,5R,6S)-6-isopropyl-3,5-dimethyltetrahydro-2H-pyran-2-one, the sex pheromone component of Macrocentrus grandii is presented. The key steps involve an enantioselective cross Aldol reaction between isobutyraldehyde and propionaldehyde, a chiral auxiliary mediated diastereoselective methylation reaction, chemoselective reduction of α,β-unsaturated ester and chemoselective oxidation reaction to get lactone. A similar strategy has been applied for the total synthesis of prelactone B.

Mechanisms and rationales of SAM homeostasis.

S-Adenosylmethionine (SAM) is the primary methyl donor for numerous cellular methylation reactions. Its central role in methylation and involvement with many pathways link its availability to the regulation of cellular processes, the dysregulation of which can contribute to disease states, such as cancer or neurodegeneration. Emerging evidence indicates that intracellular SAM levels are maintained within an optimal range by a variety of homeostatic mechanisms. This suggests that the need to maintain SAM homeostasis represents a significant evolutionary pressure across all kingdoms of life. Here, we review how SAM controls cellular functions at the molecular level and discuss strategies to maintain SAM homeostasis. We propose that SAM exerts a broad and underappreciated influence in cellular regulation that remains to be fully elucidated.

New route to preparation of loxoprofen through Mizoroki-Heck reaction as the key step

The current study describes a new preparation of loxoprofen. The whole process includes five steps from cheap cyclopentanone and methyl 4-bromophenylacetate as the starting materials. The key ­intermediate is obtained through Mizoroki-Heck reaction of 2-methylenecyclopentanone and methyl 2-(4-bromophenyl)propanoate. The desired loxoprofen is yielded through hydrogenation followed by hydrolysis in 56% overall yield with 99.7% purity.

Discovery of Spirosnuolides A-D, Type I/III Hybrid Polyketide Spiro-Macrolides for a Chemotherapeutic Lead against Lung Cancer.

Four new macrolides, spirosnuolides A-D (1-4, respectively), were discovered from the termite nest-derived Kitasatospora sp. INHA29. Spirosnuolides A-D are 18-membered macrolides sharing an embedded [6,6]-spiroketal functionality inside the macrocycle and are conjugated with structurally uncommon side chains featuring cyclopentenone, 1,4-benzoquinone, hydroxyfuroic acid, or butenolide moieties. Structure elucidation was achieved using a combination of spectroscopic analyses, multiple chemical derivatizations (methylation, methanolysis, Luche reduction, and Mosher's reaction), X-ray diffraction analysis, and computational ECD calculations. Interestingly, genome sequencing analysis suggests that spirosnuolides were biosynthesized through a rare type I/III hybrid polyketide synthase. Importantly, spirosnuolide B displayed potent antiproliferative effects against various cancer cell lines at nanomolar concentrations, particularly against HCC827 cells, an EGFR mutant non-small-cell lung cancer (NSCLC) cell line, with a high safety index value. Based on in vitro studies, the antiproliferative mechanism of spirosnuolide B involved the activation of AMPK signaling, leading to cell cycle arrest and apoptosis in HCC827 cells. Its potent efficacy was also proven in vivo by the effective inhibition of tumor growth in mouse xenograft studies. Moreover, cotreatment with spirosnuolide B and gefitinib, synergistically enhanced the antiproliferative activity and apoptosis, suggesting a potential strategy to overcome gefitinib resistance in EGFR mutant NSCLC.

Methionine Synthase Reductase A66G Variant in Pediatric Acute Lymphoblastic Leukemia Patients.

Methionine synthase reductase, which is encoded by the methionine synthase reductase (MTRR) gene, plays a crucial role in the methylation reactions and the production of DNA and its epigenetic processes. There was a correlation between the MTRR (A66G) polymorphism and the likelihood of developing acute lymphoblastic leukemia (ALL). This study was carried out to investigate the correlation among pediatric ALL cases. Within the participant population of this case-control study, there were 86 individuals who had been diagnosed with ALL, and there were also 150 healthy persons who acted as the control group. To determine the MTRR (A66G) polymorphism, DNA was first extracted and then observed through the use of real-time polymerase chain reaction. The results of the flow cytometry analysis showed that the prevalence of B-cell ALL (B-ALL) was much higher than that of T-cell ALL (T-ALL), which accounted for only 20 cases (23.3%). Upon comparing the hematological parameters of ALL subtypes in patients with T-ALL, it was discovered that there was a statistically significant higher mean total white blood count (P < 0.0005) and mean blast percentage (P = 0.050). Upon examination, it was discovered that both of these figures were much higher than the average. In accordance with the results of the molecular analysis, the occurrence of the MTRR homozygous GG genotype was found to be considerably lower in the patients' group (4.65%) than in the control group (20.67%). However, the MTRR homozygous AA and heterozygous AG were nearly similar in the two groups. The risk of acute lymphoblastic leukemia and MTRR genotypes, on the other hand, exhibited a correlation that was not statistically significant (P = 0.082). The study's findings showed that among pediatric ALL patients, the MTRR A66G polymorphism was not linked to an increased risk of ALL.

Lycorine affects tamoxifen resistance of breast cancer via m6A-based HAGLR.

N6-methyladenosine (m6A)-mediated epitranscriptomic pathway has been shown to contribute to chemoresistance and radioresistance. Our previous work confirmed the defense of lycorine against tamoxifen resistance of breast cancer (BC) through targeting HOXD antisense growth-associated long non-coding RNA (HAGLR). Whereas, the precise regulation among them remains to be elucidated. The aim of this study was to investigate the role of IGF2BP2-mediated m6A methylation in the regulation of HAGLR and its impact on lycorine's effect on tamoxifen resistance in BC. m6A status was detected via methylated RNA immunoprecipitation-quantitative polymerase chain reaction (MeRIP-qPCR). Relative expression of HAGLR and IGF2BP2 were tested by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis, respectively. Cell viability, proliferation and apoptosis were estimated via Cell Counting Kit-8 (CCK-8), colony formation and flow cytometer analysis. Interplay among IGF2BP2 and HAGLR was tested by RNA immunoprecipitation (RIP) assay. IC50 value of BC cells to tamoxifen was determined by 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Total m6A level in tamoxifen-resistant BC cells (TAMR/MCF-7 and TAMR/T47D) was elevated relative to corresponding parental cells and normal mammary epithelial cell line, MCF10A, either with the presence of m6A modifications within HAGLR sequence. Moreover, IGF2BP2-mediated m6A methylation drove the upregulation and stability of HAGLR in TAMR BC cells. IGF2BP2 served as a key downstream target mediating the anti-tumors of lycorine on TAMR BC. Knockdown of IGF2BP2 or HAGLR could reduce the IC50 value of TAMR/MCF-7 and TAMR/T47D cells to tamoxifen. Our results demonstrated that lycorine inhibits tamoxifen-resistant BC by repressing IGF2BP2-mediated m6A methylation of HAGLR.

Synthesis of an Ag-based metal–organic framework for effective capture of iodine pollutants

The effective capture of radioiodine exhausted from nuclear power plants, is of paramount importance for the radioactivity control and remediation tasks. Herein, a robust metal–organic framework Ag-Tipe integrating with open Ag+ metal sites and imidazole groups is designed for efficient capture of I2 and CH3I. The dense imidazolium groups are expected to interact with the I2 through charge transfer, enhancing the binding affinity and trapping CH3I as a reactant in the methylation reaction. In addition, the fully open silver metal center in Ag-Tipe can coordinate with iodine species to form AgI. Therefore, the Ag-Tipe exhibits high I2 and CH3I uptake capacities of 3.31 and 0.55 g/g at 75 °C, respectively. The density functional theory (DFT) calculations reveal that the I2 and CH3I binding energy at different sites in Ag-Tipe follows the order Ag > imidazole > benzene ring. This work demonstrates the important role of the binding site of the adsorbent in achieving high I2/CH3I trapping performance.

M6A-modified circCacna1c regulates necroptosis and ischemic myocardial injury by inhibiting Hnrnpf entry into the nucleus

BackgroundCircular RNAs (circRNAs) are differentially expressed in various cardiovascular diseases, including myocardial infarction (MI) injury. However, their functional role in necroptosis-induced loss of cardiomyocytes remains unclear. We identified a cardiac necroptosis-associated circRNA transcribed from the Cacna1c gene (circCacna1c) to investigate the involvement of circRNAs in cardiomyocyte necroptosis.MethodsTo investigate the role of circCacna1c during oxidative stress, H9c2 cells and neonatal rat cardiomyocytes were treated with hydrogen peroxide (H2O2) to induce reactive oxygen species (ROS)-induced cardiomyocyte death. The N6-methyladenosine (m6A) modification level of circCacna1c was determined by methylated RNA immunoprecipitation quantitative polymerase chain reaction (MeRIP–qPCR) analysis. Additionally, an RNA pull-down assay was performed to identify interacting proteins of circCacna1c in cardiomyocytes, and the regulatory role of circCacna1c in target protein expression was tested using a western blotting assay. Furthermore, the MI mouse model was constructed to analyze the effect of circCacna1c on heart function and cardiomyocyte necroptosis.ResultsThe expression of circCacna1c was found to be reduced in cardiomyocytes exposed to oxidative stress and in mouse hearts injured by MI. Overexpression of circCacna1c inhibited necroptosis of cardiomyocytes induced by hydrogen peroxide and MI injury, resulting in a significant reduction in myocardial infarction size and improved cardiac function. Mechanistically, circCacna1c directly interacts with heterogeneous nuclear ribonucleoprotein F (Hnrnpf) in the cytoplasm, preventing its nuclear translocation and leading to reduced Hnrnpf levels within the nucleus. This subsequently suppresses Hnrnpf-dependent receptor-interacting protein kinase 1 (RIPK1) expression. Furthermore, fat mass and obesity-associated protein (FTO) mediates demethylation of m6A modification on circCacna1c during necrosis and facilitates degradation of circCacna1c.ConclusionOur study demonstrates that circCacna1c can improve cardiac function following MI-induced heart injury by inhibiting the Hnrnpf/RIPK1-mediated cardiomyocyte necroptosis. Therefore, the FTO/circCacna1c/Hnrnpf/RIPK1 axis holds great potential as an effective target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.Graphical

Metabolic regulation of RNA methylation by the m6A-reader IGF2BP3.

The interplay of RNA modifications - deposited by "writers", removed by "erasers" and identified by RNA binding proteins known as "readers" - forms the basis of the epitranscriptomic gene regulation hypothesis. Recent studies have identified the oncofetal RNA-binding protein IGF2BP3 as a "reader" of the N6-methyladenosine (m6A) modification and crucial for regulating gene expression. Yet, how its function as a reader overlaps with its critical oncogenic function in leukemia remains an open question. Here, we report the novel finding that the reader IGF2BP3 reprograms cellular metabolism, resulting in an altered ability of the "writers" to modify the epitranscriptome. In leukemia cells, IGF2BP3 supports increased glycolytic flux and one-carbon metabolism, leading to increased production of S-adenosyl methionine (SAM), a key substrate for methylation reactions within the cell. IGF2BP3 directly regulates the translation of MAT2B, the regulatory subunit of the methionine-adenosyltransferase complex, which is the final enzyme in a pathway leading to SAM production. This, in turn, results in increased m6A modifications on RNA, resulting in positive feedback regulation. This novel mechanism illustrates how metabolism mutually acts with epitranscriptomic modifications, underscoring the pervasive impact of IGF2BP3 in gene regulatory mechanisms governing a broad range of cancer-specific processes.

Examining prestructured β-actin peptides as substrates of histidine methyltransferase SETD3

The Nτ-His73 methylation of β-actin by histidine methyltransferase SETD3 is required for the integrity of the cellular cytoskeleton. Modulation of SETD3 activity in human cells facilitates cancer-like changes to the cell phenotype. SETD3 binds β-actin in an extended conformation, with a conserved bend-like motif surrounding His73. Here, we report on the catalytic specificity of SETD3 towards i, i + 3 stapled β-actin peptides possessing a limited conformational freedom surrounding the His73 substrate residue via positions Glu72 and Ile75. Stapled β-actin peptides were observed to be methylated less efficiently than the linear β-actin peptide. None of the stapled β-actin peptides efficiently inhibited the SETD3-catalyzed Nτ-His73 methylation reaction. Molecular dynamics simulations demonstrated that the unbound and SETD3-bound β-actin peptides display different backbone flexibility and bend-like conformations, highlighting their important role in substrate binding and catalysis. Overall, these findings suggest that reduced backbone flexibility of β-actin prevents the formation of optimal protein-peptide interactions between the enzyme and substrate, highlighting that the backbone flexibility needs to be considered when designing β-actin-based probes and inhibitors of biomedically important SETD3.

Palladium-Catalyzed Cascade Distal C-H Methylation and Cyclization for the Construction of Spirooxindole Skeletons.

Transition metal-catalyzed C-H methylation represents a straightforward approach for introducing methyl groups into organic molecules. Herein, we report a palladium-catalyzed alkene-relayed remote C-H methylation reaction that utilizes dimethyl carbonate as the methylation reagent. The aryl groups distal to a bromo group were dimethylated via C-H activation, leading to the formation of spirooxindoles as the final products through C(sp3)-H activation and C(sp3)-C(sp3) coupling. This cascade process involves the formation of four C-C bonds and the activation of three C-H bonds. The reaction not only provides a new approach to C-H methylation but also offers a novel method for constructing spirooxindole skeletons by merging skeleton construction and methylation into a single step.

Doping In Vivo Alkylation in E. coli by Introducing the Direct Sulfurylation Pathway of S. cerevisiae

AbstractMethylation and alkylation are important techniques used for the synthesis and derivatisation of small molecules and natural products. Application of S‐adenosylmethionine (SAM)‐dependent methyltransferases (MTs) in biotechnological hosts such as Escherichia coli lowers the environmental impact of alkylation compared to chemical synthesis and facilitates regio‐ and chemoselective alkyl chain transfer. Here, we address the limiting factor for SAM synthesis, methionine supply, to accelerate in vivo methylation activity. Introduction of the direct sulfurylation pathway, consisting of O‐acetylhomoserine sulfhydrolase (ScOAHS) and O‐acetyltransferase (ScMET2), from S. cerevisiae into E. coli and supplementation with methanethiol or the corresponding disulfide improves atom‐economic methylation activity in three different MT reactions. Up to 17‐fold increase of conversion compared to the sole expression of the MT and incorporation of up to 79 % of the thiol compound added were achieved. Promiscuity of ScOAHS allowed in vivo production of methionine analogues from organic thiols. Further co‐overproduction of a methionine adenosyltransferase yielded SAM analogues which were further transferred by MTs onto different substrates. For methylation of non‐physiological substrates, conversion rates up to 73 % were achieved, with an isolated yield of 41 % for N‐methyl‐2,5‐aminonitrophenol. The here described technique enables E. coli to become a biotechnological host for improved methylation and selective alkylation reactions.

Doping In Vivo Alkylation in E. coli by Introducing the Direct Sulfurylation Pathway of S. cerevisiae.

Methylation and alkylation are important techniques used for the synthesis and derivatisation of small molecules and natural products. Application of S-adenosylmethionine (SAM)-dependent methyltransferases (MTs) in biotechnological hosts such as Escherichia coli lowers the environmental impact of alkylation compared to chemical synthesis and facilitates regio- and chemoselective alkyl chain transfer. Here, we address the limiting factor for SAM synthesis, methionine supply, to accelerate in vivo methylation activity. Introduction of the direct sulfurylation pathway, consisting of O-acetylhomoserine sulfhydrolase (ScOAHS) and O-acetyltransferase (ScMET2), from S. cerevisiae into E. coli and supplementation with methanethiol or the corresponding disulfide improves atom-economic methylation activity in three different MT reactions. Up to 17-fold increase of conversion compared to the sole expression of the MT and incorporation of up to 79 % of the thiol compound added were achieved. Promiscuity of ScOAHS allowed in vivo production of methionine analogues from organic thiols. Further co-overproduction of a methionine adenosyltransferase yielded SAM analogues which were further transferred by MTs onto different substrates. For methylation of non-physiological substrates, conversion rates up to 73 % were achieved, with an isolated yield of 41 % for N-methyl-2,5-aminonitrophenol. The here described technique enables E. coli to become a biotechnological host for improved methylation and selective alkylation reactions.

Sustainable C-H Methylation Employing Dimethyl Carbonate.

The use of CO2 and CO2-derived chemicals offers society sustainable and biocompatible chemistry for a variety of applications, ranging from materials to medicines. In this context, dimethyl carbonate (DMC) stands out owing to its low toxicity, high biodegradability, tunable reactivity, and sustainable production. Further, the ability of DMC to act as an ambient electrophile at varied temperatures and reaction conditions in order to produce methoxycarbonylated (via BAC2) and methylated products (via BAL2) is very promising. While the methylation of hetero-H (N-, O-, and S-methylation) with DMC is established and well-reviewed, the C-H methylation reaction with DMC is limited, and there is no specific literature detailing the C-methylation reaction using DMC, creating new opportunities as well as challenges in the same domain. In this context, the present perspective focuses on the new breakthroughs, recent advances, and trends in C-H methylation reactions employing DMC. A critical analysis of the mechanistic course of reactions under each category was undertaken. We believe this timely perspective will offer an in-depth analysis of existing literature with critical remarks, which will certainly inspire fellow researchers across disciplines to understand and pursue cutting-edge research in the area of C-H methylation (alkylation) using DMC and related organic carbonates.