Amino Aldehydes Research Articles

Rapid and practical synthesis of N-protected amino ketones in continuous flow via pre-deprotonation protocol

Rapid and practical synthesis of N-protected amino ketones in continuous flow via pre-deprotonation protocol

Gas chromatography-mass spectrometry analysis of metabolites in finger millet and Bambara groundnut as affected by traditional and novel food processing.

Metabolite profiling is an analytical technique used to assess metabolites in complex biological samples. This technique allows for the identification of both targeted and untargeted metabolites. In this study, the effect of traditional (fermentation and malting) and novel processing (ultrasonication) on the metabolites of finger millet (FM) and Bambara groundnut (BGN) flour was investigated using gas chromatography-mass spectrometry. Various metabolite classes, including amino acids, alcohol, aldehyde, organic acid, ester, fatty acids, glycoside, and sugar, were identified in FM and BGN flours. The adopted processing techniques impacted metabolite composition, as evidenced by substantial variations in volatile compound levels and metabolite composition among the FM and BGN samples before and after traditional and novel processing. Important health-promoting compounds, such as oleic acid, linoelaidic acid, and linoleic acid, were identified at their highest levels in fermented FM and BGN flours. The results obtained from this study offer an important context for monitoring and regulating the metabolite composition of FM and BGN flours under traditional and novel processing. PRACTICAL APPLICATION: Fermentation, malting, and ultrasonication induced desirable changes in some health-promoting compounds of finger millet and Bambara groundnut flours. The food and pharmaceutical industries could benefit from these traditional- and novel-modified flours as they could be used as improved food sources with health benefits.

Visible-Light-Promoted Enantioselective Acylation and Alkylation of Aldimines Enabled by 9-Fluorenone Electron-Shuttle Catalysis.

Chiral acyclic α-tertiary amino ketones are widely present in various natural products and pharmaceuticals; however, the direct synthesis of this pharmacophore through a robust strategy still presents significant challenges. The emerging photocatalysis provides a powerful approach to construct chemical bonds that are difficult to form via a traditional two-electron pathway. Herein, we developed visible-light-induced chiral Lewis acid-catalyzed highly enantioselective acylation/alkylation of aldimines enabled by cooperative FLN (9-fluorenone) electron-shuttle catalysis via radical addition. An array of α-tertiary amino ketones, β-amino alcohols, and chiral amines were achieved with high yields and good to excellent stereocontrol (87 examples, up to 84% yield, 96% ee). These products can be easily transformed into valuable and bioactive skeletons. Extensive control experiments, detailed mechanism studies, and density functional theory calculations elucidated the reaction process and highlighted the crucial role played by FLN.

Investigating the etiology of Haff disease: Optimization and validation of a sensitive LC-MS/MS method for palytoxins analysis in directly associated freshwater and marine food samples from Brazil

Haff disease typically develops after eating contaminated marine or freshwater species, especially fish. Despite still having an unknown etiology, recent reports have suggested its possible correlation with palytoxins. Therefore, the present work aimed to optimize and perform a validation of a sensitive method using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) for the analysis of palytoxin and some of its analogs, with the main purpose of investigating their presence in marine and freshwater food samples associated with Haff disease in Brazil. The method optimization was performed using a central composite rotatable design and fish samples fortified with the palytoxin standard. Then, the optimized method was validated for different food matrices, including freshwater and marine fish, mollusks, and crustaceans. The sample preparation involved a solid–liquid extraction using methanol and water, solid-phase extraction using Strata-X cartridges, and on-column palytoxin oxidation. The detection of the main oxidized fragments (amino and amide aldehydes) was achieved by LC-MS/MS with electrospray ionization in positive mode, using a C18 column, as well as acetonitrile and water as mobile phases, both acidified with 0.1 % of formic acid. After optimization and validation, the etiological investigation involved the analysis of 16 Brazilian Haff disease-related food samples (in natura and leftover meals) from 2022. The method was demonstrated to be appropriate for quantitative analysis of freshwater and marine species. So far, it has proven to be one of the most sensitive methods related to palytoxin detection (LOD 10 μg/kg), being able to work in a range that includes the provisional ingestion limit (30 μg/kg). Regarding the Haff disease-related samples analysis, there is a strong indication of palytoxin contamination since the amino aldehyde (common fragment for all palytoxins) was detected in 15 of the 16 samples. Selected results were confirmed using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS).

Circulating metabolic biomarkers and risk of new-onset hypertension: findings from the UK Biobank.

The evidence regarding the associations of circulating metabolic biomarkers with hypertension risk is scarce. We aimed to examine the associations between circulating metabolites and risk of hypertension. We included 49 422 individuals free of hypertension at baseline with a mean (SD) age of 53.5 (8.0) years from the UK Biobank. Nuclear magnetic resonance spectroscopy was used to quantify 143 individual metabolites. Multivariable-adjusted Cox regression models were used to estimate hazard ratios and 95% confidence intervals (CIs). During a mean (SD) follow-up of 11.2 (1.8) years, 2686 incident hypertension cases occurred. Out of 143 metabolites, 76 were associated with incident hypertension, among which phenylalanine (hazard ratio: 1.40; 95% CI: 1.24-1.58) and apolipoprotein A1 (hazard ratio: 0.76; 95% CI: 0.66-0.87) had the strongest association when comparing the highest to the lowest quintile. In general, very-low-density lipoprotein (VLDL) particles were positively, whereas high-density lipoprotein (HDL) particles were inversely associated with risk of hypertension. Similar patterns of cholesterol, phospholipids, and total lipids within VLDL and HDL particles were observed. Triglycerides within all lipoproteins were positively associated with hypertension risk. Other metabolites showed significant associations with risk of hypertension included amino acids, fatty acids, ketone bodies, fluid balance and inflammation markers. Adding 10 selected metabolic biomarkers to the traditional hypertension risk model modestly improved discrimination (C-statistic from 0.745 to 0.752, P < 0.001) for prediction of 10-year hypertension incidence. Among UK adults, disturbances in metabolic biomarkers are associated with incident hypertension. Comprehensive metabolomic profiling may provide potential novel biomarkers to identify high-risk individuals.

Chemo-, regio-, and stereoselective catalyst-free addition of diphenylphosphine oxide to acetylenic amino ketones. Synthesis of Z-diphenylphosphoryl(organylamino)alkenones

Chemo-, regio-, and stereoselective catalyst-free addition of diphenylphosphine oxide to acetylenic amino ketones. Synthesis of Z-diphenylphosphoryl(organylamino)alkenones

Ultrasound-Assisted Catalyst-free Synthesis of α,β -Unsaturated Amino Acid Esters and Unsaturated Amino Ketones

Introduction: Sonication has been introduced as a green and effective activation method for the selective monoamination of β-dicarbonyl compounds. The simple one-pot process resulted in different substituted β-amino-ɑ,β-unsaturated esters and ketones at room temperature with quantitative yields. Aqueous NH4OH was used as a safe and economical nitrogen source for pressurized NH3 gas. The process is considered green, accounting for not using any solvents and catalysts, besides some aqueous NH4OH-involved reactions using nontoxic water. A broad variety of useful synthetic intermediates, β- amino-ɑ,β-unsaturated esters and ketones have been prepared in short reaction time. Methods: Using this developed protocol, we were able to synthesize a series of structurally diverse β- amino-ɑ,β-unsaturated esters and unsaturated amino ketones. Results: The synthesis of target compounds was achieved in a truly green process with high atom economy and excellent yields in a catalyst-free one-pot system in an aqueous medium using simple, commercially available, inexpensive ammonium hydroxide as the source of the nitrogen. The high atom economy has been accompanied by the formation of a small amount of nontoxic waste, water. Conclusion: In conclusion, a simple, convenient, and high-yielding catalyst-free environmentally benign method was developed for the synthesis of unsaturated amino acid esters and unsaturated amino ketones.

Copper-Catalyzed Three-Component Synthesis of Highly Substituted Morpholines.

Unprotected, highly substituted morpholines were obtained through a copper-catalyzed three-component reaction utilizing amino alcohols, aldehydes, and diazomalonates. The transformation was effective for diversely substituted aldehydes and for a broad range of readily available vicinal amino alcohols, including those derived from glycine, α-substituted, and α,α-disubstituted amino acids. Epimerization of morpholines using light-mediated stereochemical editing was demonstrated, and the unprotected morpholine products were readily elaborated through efficient transformations.

Copper(II) Triflate Catalyzed Rearrangement of Amino 2,3-Epoxides to α-Amino Ketones

Abstractα-Amino ketones were synthesized by a Meinwald rearrangement of biomass-based amino epoxides using copper(II) triflate as a catalyst. The regioselectivity of the rearrangement can be rationalized in terms of the reaction proceeding via the most stable carbocationic intermediate to give various α-amino α′-aryl ketones in moderate to good yields. This is an attractive method to prepare α-amino ketones using a benign and inexpensive catalyst.

Rust Prevention Property of a New Organic Inhibitor under Different Conditions.

The corrosion resistance properties of a new type of environmentally-friendly organic inhibitor containing amino ketone molecules are presented in this paper. To evaluate the prevention effect of the inhibitor on corrosion of reinforcement, the electrochemical characteristics of steels in the simulated concrete pore solution (SPS) were investigated under varied conditions of the relevant parameters, including concentrations of the inhibitor and NaCl, pH value, and temperature. The inhibition efficiency of the material was characterized through electrochemical impedance spectroscopy (EIS), potentiodynamic polarization, and the weight loss of steels. The results reveal a significant improvement in the corrosion resistance of steels with the inhibitor. A maximum resistance value of 89.07% was achieved at an inhibitor concentration of 4%. Moreover, the new organic inhibitor exhibited good corrosion protection capability for steels under different NaCl concentrations. Its inhibition efficiency was determined to be 65.62, 80.06, and 66.30% at NaCl concentrations of 2, 3.5 and 5%, respectively. On the other hand, it was found that an alkaline environment was favorable for an enhanced corrosion prevention effect, and an optimal pH value of 11.3 was observed in this work. Besides, the inhibition efficiencies at different temperatures showed a trend of 25 > 35 > 40 > 20 > 30 °C, with a maximum value of 81.32% at 25 °C. The above results suggest that the new organic material has high potential to be used as an eco-friendly and long-term durable inhibitor for steel corrosion prevention under complex conditions.

Synthesis of bio-based polyimine networks with flame-retardancy, acid-degradablility, and reprocessability

Conventional thermosetting materials lack of reprocessability, acid-degradability, and fire-safety, which limit the further popularization and application of materials. In this study, a hexasubstituted cyclotriphosphazene (HVP) was synthesized from abundant renewable vanillin, and then combined with two bio-based amines (castor oil polyamine and furan-derived diamine) to establish polyimine networks through a condensation reaction between amino groups and aldehyde groups. Five bio-based polyimine thermoset networks (FA-0, FA-25, FA-50, FA-75, and FA-100) were prepared with an ammonia-formaldehyde ratio of 1:1, and varying the ratio of the two bio-based amines allowed for regulating the final mechanical properties (from tough plastic-like to hard plastic-like) and flame resistance of the materials. Among the five experimental samples, FA-100 exhibited the best physical properties stress and Tg of 28.47 MPa and 63.8 °C, respectively. FA-100 networks also showed the best flame retardant properties (LOI, 28.8 vol/%). Furthermore, due to the dynamic imine bonds in the polymer network, the material could be recycled under hot pressing conditions (120 °C and 15 MPa). Meanwhile, the monomer HVP could be recovered under mild acidic circumstances. These thermosetting polyimine networks provide a new avenue for the development of multifunctional bio-based polymer materials for practical applications.

Incremental Value of a Metabolic Risk Score for Heart Failure Mortality: A Population-Based Study.

Heart failure is heterogeneous syndrome with persistently high mortality. Nuclear magnetic resonance spectroscopy enables high-throughput metabolomics, suitable for precision phenotyping. We aimed to use targeted metabolomics to derive a metabolic risk score (MRS) that improved mortality risk stratification in heart failure. Nuclear magnetic resonance was used to measure 21 metabolites (lipoprotein subspecies, branched-chain amino acids, alanine, GlycA (glycoprotein acetylation), ketone bodies, glucose, and citrate) in plasma collected from a heart failure community cohort. The MRS was derived using least absolute shrinkage and selection operator penalized Cox regression and temporal validation. The association between the MRS and mortality and whether risk stratification was improved over the Meta-Analysis Global Group in Chronic Heart Failure clinical risk score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels were assessed. The study included 1382 patients (median age, 78 years, 52% men, 43% reduced ejection fraction) with a 5-year survival rate of 48% (95% CI, 46%-51%). The MRS included 9 metabolites measured. In the validation data set, a 1 standard deviation increase in the MRS was associated with a large increased rate of death (hazard ratio, 2.2 [95% CI, 1.9-2.5]) that remained after adjustment for Meta-Analysis Global Group in Chronic Heart Failure score and NT-proBNP (hazard ratio, 1.6 [95% CI, 1.3-1.9]). These associations did not differ by ejection fraction. The integrated discrimination and net reclassification indices, and Uno's C statistic, indicated that the addition of the MRS improved discrimination over Meta-Analysis Global Group in Chronic Heart Failure and NT-proBNP. This MRS developed in a heart failure community cohort was associated with a large excess risk of death and improved risk stratification beyond an established risk score and clinical markers.

Domino Reaction Protocol to Synthesize Benzothiophene-Derived Chemical Entities as Potential Therapeutic Agents.

An efficient synthesis of 3-amino-2-formyl-functionalized benzothiophenes by a domino reaction protocol and their use to synthesize a library of novel scaffolds have been reported. Reactions of ketones and 1,3-diones with these amino aldehyde derivatives formed a series of benzothieno[3,2-b]pyridine and 3,4-dihydro-2H-benzothiopheno[3,2-b]quinolin-1-one, respectively. A plausible mechanism for the formation of fused pyridine derivatives by the Friedlander reaction has been elucidated by density functional theory (DFT) calculations. Furthermore, hydrazones were obtained by reacting the aldehyde functional group of benzothiophenes with different hydrazine derivatives. Preliminary screening of these compounds against several bacterial strains and cancer cell lines led to the discovery of several hit molecules. Hydrazone and benzothieno[3,2-b]pyridine derivatives are potent cytotoxic and antibacterial agents, respectively. One of the potent compounds effected ∼97% growth inhibition of the LOX IMVI cell line at 10 μM concentration.

Metal-Free One-Pot Domino Synthesis of Oxazolidinethione Derivatives of Quaternary Amino Acids from α-Amino Esters and Aldehydes Using CS2.

We present a streamlined, metal-free, one-pot domino approach to efficiently synthesize oxazolidinethione derivatives containing substituted quaternary amino acids. This method employs α-amino esters, aldehydes, and CS2 under mild conditions, constructing three new bonds (C-N, C-C, and C-O) to produce oxazolidinethione compounds featuring a quaternary center and a beta-hydroxy derivative in high yields. This scalable protocol enables the creation of libraries of biologically significant, intricate amino acid derivatives using amino esters and aldehydes.

Circulating metabolome landscape in Lynch syndrome.

Circulating metabolites systemically reflect cellular processes and can modulate the tissue microenvironment in complex ways, potentially impacting cancer initiation processes. Genetic background increases cancer risk in individuals with Lynch syndrome; however, not all carriers develop cancer. Various lifestyle factors can influence Lynch syndrome cancer risk, and lifestyle choices actively shape systemic metabolism, with circulating metabolites potentially serving as the mechanical link between lifestyle and cancer risk. This study aims to characterize the circulating metabolome of Lynch syndrome carriers, shedding light on the energy metabolism status in this cancer predisposition syndrome.This study consists of a three-group cross-sectional analysis to compare the circulating metabolome of cancer-free Lynch syndrome carriers, sporadic colorectal cancer (CRC) patients, and healthy non-carrier controls. We detected elevated levels of circulating cholesterol, lipids, and lipoproteins in LS carriers. Furthermore, we unveiled that Lynch syndrome carriers and CRC patients displayed similar alterations compared to healthy non-carriers in circulating amino acid and ketone body profiles. Overall, cancer-free Lynch syndrome carriers showed a unique circulating metabolome landscape.This study provides valuable insights into the systemic metabolic landscape of Lynch syndrome individuals. The findings hint at shared metabolic patterns between cancer-free Lynch syndrome carriers and CRC patients.

Redox-economical synthesis of α-substituted α-N-phthaloyl amino aldehydes using Fukuyama reduction

A three-step redox-economical synthesis of α-substituted α-N-phthaloyl aldehydes was developed using Fukuyama reduction from commercially available amino acids. The developed method provided various α-substituted α-N-phthaloyl aldehydes (16 entries) in 29–98 % yields. The developed protocol was reproducible on a large scale.

Hepatic glucagon action: beyond glucose mobilization.

Glucagon's ability to promote hepatic glucose production has been known for over a century, with initial observations touting this hormone as a diabetogenic agent. However, glucagon receptor agonism [when balanced with an incretin, including glucagon-like peptide 1 (GLP-1) to dampen glucose excursions] is now being developed as a promising therapeutic target in the treatment of metabolic diseases, like metabolic dysfunction-associated steatotic disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH), and may also have benefit for obesity and chronic kidney disease. Conventionally regarded as the opposing tag-team partner of the anabolic mediator insulin, glucagon is gradually emerging as more than just a "catabolic hormone." Glucagon action on glucose homeostasis within the liver has been well characterized. However, growing evidence, in part thanks to new and sensitive "omics" technologies, has implicated glucagon as more than just a "glucose liberator." Elucidation of glucagon's capacity to increase fatty acid oxidation while attenuating endogenous lipid synthesis speaks to the dichotomous nature of the hormone. Furthermore, glucagon action is not limited to just glucose homeostasis and lipid metabolism, as traditionally reported. Glucagon plays key regulatory roles in hepatic amino acid and ketone body metabolism, as well as mitochondrial turnover and function, indicating broader glucagon signaling consequences for metabolic homeostasis mediated by the liver. Here we examine the broadening role of glucagon signaling within the hepatocyte and question the current dogma, to appreciate glucagon as more than just that "catabolic hormone."

Changes in Isoleucine, Sarcosine, and Dimethylglycine During OGTT as Risk Factors for Diabetes.

Current metabolomics studies in diabetes have focused on the fasting state, while only a few have addressed the satiated state. We combined the oral glucose tolerance test (OGTT) and metabolomics to examine metabolite-level changes in populations with different glucose tolerance statuses and to evaluate the potential risk of these changes for diabetes. We grouped participants into those with normal glucose tolerance (NGT), impaired glucose regulation (IGR), and newly diagnosed type 2 diabetes (NDM). During the OGTT, serum was collected at 0, 30, 60, 120, and 180 minutes. We evaluated the changes in metabolite levels during the OGTT and compared metabolic profiles among the 3 groups. The relationship between metabolite levels during the OGTT and risk of diabetes and prediabetes was analyzed using a generalized estimating equation (GEE). The regression results were adjusted for sex, body mass index, fasting insulin levels, heart rate, smoking status, and blood pressure. Glucose intake altered metabolic profile and induced an increase in glycolytic intermediates and a decrease in amino acids, glycerol, ketone bodies, and triglycerides. Isoleucine levels differed between the NGT and NDM groups and between the NGT and IGR groups. Changes in sarcosine levels during the OGTT in the diabetes groups were opposite to those in glycine levels. GEE analysis revealed that during OGTT, isoleucine, sarcosine, and acetic acid levels were associated with NDM risks, and isoleucine and acetate levels with IGR risks. Metabolic profiles differ after glucose induction in individuals with different glucose tolerance statuses. Changes in metabolite levels during OGTT are potential risk factors for diabetes development.

Constitutional adaptation to pKa modulation by remote ester hydrolysis.

The mechanisms through which environmental conditions affect the expression of interconnected species is a key step to comprehending the principles underlying complex chemical processes. In Nature, chemical modifications triggered by the environment have a major impact on the structure and function of biomolecules and regulate different reaction pathways. Yet, minimalistic artificial systems implementing related adaptation behaviours remain barely explored. The hydrolysis of amino acid methyl esters to their corresponding amino acids leads to a drastic change in pKa (ca. 7 and 9, respectively) that protonates the free amino group at physiological conditions. Dynamic covalent libraries (DCvLs) based on amino acid methyl esters and aldehydes respond to such hydrolysis and lead to constitutional adaptation. Each of the libraries studied experiences a DCvL conversion allowing for constituent selection due to the silencing of the zwitterionic amino acids towards imine formation. The selective action of different enzymes on the DCvLs results in states with simplified constitutional distributions and transient chirality. When additional components (i.e., scavengers) that are not affected by hydrolysis are introduced into the dynamic libraries, the amino acid methyl ester hydrolysis induces the up-regulation of the constituents made of these scavenging components. In these systems, the constituent distribution is resolved from a scrambled mixture of imines to a state characterized by the predominance of a single aldimine. Remarkably, although the final libraries display higher "simplexity", the different transient states present an increased complexity that allows for the emergence of organized structures [micelle formation] and distributions [up-regulation of two antagonistic constituents]. This reactive site inhibition by a remote chemical modification resembles the scenario found in some enzymes for the regulation of their activity through proximal post-translational modifications.

A Direct Synthesis of Substituted Exocyclic 1H‐pyrrol‐3(2H)‐ones by Base‐Mediated Multicomponent [3+2] Cycloaddition

AbstractA one‐pot, three‐component, base‐mediated [3+2] cycloaddition reaction to synthesize 1H‐pyrrol‐3(2H)‐ones from readily available amino acid esters, aldehydes, and terminal alkynes was reported. Isolation of the intermediate and the detailed mechanistic study revealed the course of the reaction. This multi‐component reaction proceeds via imine formation followed by the nucleophilic addition of alkyne to form a propargylamine precursor. Base‐mediated conversion of propargylamine precursor into 1‐azadiene followed by in situ ketene formation leading to [3+2] cycloaddition that ultimately produces unusual 1H‐pyrrol‐3(2H)‐ones.