Amino Aldehydes Research Articles

Maximizing Step-Normalized Increases in Molecular Complexity: Formal [4+2+2+2] Photoinduced Cyclization Cascade to Access Polyheterocycles Possessing Privileged Substructures.

A new complexity building photoinduced cascade which amounts to an unprecedented formal [4+2+2+2] cycloaddition topology is developed to access complex nitrogen polyheterocycles. This photocascade is initiated by the excited state intramolecular proton transfer (ESIPT) in aromatic amino ketones with tethered dual unsaturated pendants, i.e. pyrrole and alkenic moieties, resulting in the formation of four σ-bonds and setting six new stereogenic centers in a single experimentally simple photochemical step with up to 220 mcbit complexity increases.

Friedländer, Knoevenagel, and Michael Reactions Employing the Same MOF: Synthesis, Structure, and Heterogeneous Catalytic Studies of ([Zn(1,4-NDCA)(3-BPDB)0.5]·(DMF)(MeOH) and [Cd4(1,4-NDCA)4(3-BPDB)4]·2(DMF)

Two new inorganic–organic coordination polymers, namely, ([Zn(1,4-NDCA)(3-BPDB)0.5]·(DMF)(MeOH) (I) and [Cd4(1,4-NDCA)4(3-BPDB)4]·2(DMF) (II), were synthesized by employing naphthalene dicarboxylic acid and 1,4-bis(3-pyridyl)-2,3-diaza-1,3-butadiene (3-BPDB) ligands. Both the compounds have a three-dimensional structure and exhibit Lewis acidic as well as basic characters. The Lewis acid character was explored by using the Friedländer reaction involving the condensation of amino benzaldehyde and ketones. The Lewis basic character was investigated by employing a three-component condensation that combines Knoevenagel and Michael reactions. Both the Lewis acid and Lewis base reactions were found to proceed well, giving rise to the expected products with good and comparable yields of ∼80%. The catalysts were found to be active for up to three cycles.

Construction of Thioamide Peptide via Sulfur-Involved Amino Acids/Amino Aldehydes Coupling.

A sulfur-involved ligation for thioamide quasi-peptides was developed via amino acids and amino aldehydes coupling. The key to the transformation was the chelation of copper with imines for chiral activation and fixation. In this environment, linear polysulfur decreased the alkalinity of single sulfur anions to prevent racemization caused by the interaction between sulfur and sodium sulfide. Dipeptides, tripeptides, tetrapeptides, and the linkage between the drug and amino acids were successfully obtained.

Synthesis of modified amino-aldehyde oligo (poly) mers and study of their thermal stability

In the article are discussed the relevance of obtaining amino aldehyde oligomers and the study of their basic physicochemical properties and determines that the synthesis conditions and the ratio of the starting components play an important role on the properties and structure of the synthesized amino aldehyde oligomers. Using the Differential thermal analysis (DTA) method, it was proved that the modification of the urea-formaldehyde oligomer with acrylic acid helps to increase the thermal oxidative degradation of the resulting products. In this case, the modifier - acrylic acid strongly chemically binds with amino aldehyde oligomers, which leads to an increase in the heat resistance of the samples.

Lipid and metabolite correlation networks specific to clinical and biochemical covariate show differences associated with sexual dimorphism in a cohort of nonagenarians

This study defines and estimates the metabolite-lipidic component association networks constructed from an array of 20 metabolites and 114 lipids identified and quantified via NMR spectroscopy in the serum of a cohort of 355 Italian nonagenarians and ultra-nonagenarian. Metabolite-lipid association networks were built for men and women and related to an array of 101 clinical and biochemical parameters, including the presence of diseases, bio-humoral parameters, familiarity diseases, drugs treatments, and risk factors. Different connectivity patterns were observed in lipids, branched chains amino acids, alanine, and ketone bodies, suggesting their association with the sex-related and sex-clinical condition-related intrinsic metabolic changes. Furthermore, our results demonstrate, using a holistic system biology approach, that the characterization of metabolic structures and their dynamic inter-connections is a promising tool to shed light on the dimorphic pathophysiological mechanisms of aging at the molecular level.

Unexpected dihydropyridinium derivatives using a multicomponent reaction containing unprotected amino acids

In this study, a multicomponent reaction (MCR) of amino acids, aldehydes, β-dicarbonyl compounds, and malononitrile is presented to obtain a novel class of dihydropyridinium scaffolds which are incorporating amino acid moieties. Some derivatives were obtained in tetrahydropyrido[2,3-d]pyrimidin form. The reaction proceeded through formation of a stable enolate as triethylammoniumenolate salt, which is isolable from the reaction mixture. The DFT calculations also confirm the stability of the formed dihydropyridinium structure. The docking studies of the synthesized compounds on the acetylcholinesterase target (PDB ID = 5FUM) show high potential inhibitory activities of these compounds in Alzheimer's disease.

Triethylammonium Hydrogen Sulfate [Et3NH][HSO4]-Catalyzed Rapid and Efficient Multicomponent Synthesis of Pyrido[2,3-d]pyrimidine and Pyrazolo[3,4-b]pyridine Hybrids.

An operationally simple, one-pot multicomponent reaction has been developed for the assembly of pyrido[2,3-d]pyrimidine and pyrazolo[3,4-b]pyridine derivatives (4a–4am) in excellent yields (92–94%) with high purity. The reactions were easy to perform simply by mixing of electron-rich amino heterocycles (including aminouracils and aminopyrazoles), aldehyde, and acyl acetonitrile in the presence of [Et3NH][HSO4] under solvent-free conditions. The remarkable feature of the present approach is that the ionic liquid possesses dual solvent-catalytic engineering capability. Results of this study revealed that 1 mmol of the ionic liquid catalyst under solvent-free conditions at 60 °C is the best reaction parameter for the construction of fused pyridine and pyrimidine derivatives in excellent yields. The present methodology showed good results under gram-scale conditions, thereby indicating its applicability in industrial as well as academic settings in the near future.

A rapid LC-MS/MS method for simultaneous determination of nicotine and its key derivatives including hydroxylation isomers

A rapid high pressure liquid chromatography coupled with tandem mass spectrometry method (LC-MS/MS) was developed for simultaneously determining nicotine (NT) and its derivatives including cotinine (CT), trans-3-hydroxycotinine (HC), nornicotine (NNT), anatabine (AT), anabasine (AB) and amino ketone (4-(methylamino)-1-(3-pyridyl)1-butanone) (AK) as well as two important metabolites isomers 2-hydroxynicotine (2-HN) and 6-hydroxynicotine (6-HN) in tobacco leaves. Different from other methods, 2-HN and 6-HN isomers can be successfully separated and quantified through a combination of amide and C18 columns and optimized multiple reaction monitoring mode of tandem mass spectrometry. The limits of detections (LOD) and quantification (LOQ) of these compounds were 0.02 and 0.06 ng/mL for CT and HC, 0.05 and 0.15 ng/mL for AK and 6-HN, and 0.1 and 0.3 ng/mL for AB, NNT, AT, 2-HN and NT, respectively. Their recoveries ranged from 86.1% for 2-HN to 102.2% for AK by using solvent extraction assisted with ultrasonication. The developed method was validated through determination of the compounds in different regular and genetically modified (for lowering nicotine) tobacco leaves. Conclusively, it is a robust and rapid method for simultaneous quantification of nicotine and its derivatives in tobacco products. The protocol of the method could also be applied in developing analysis method for tracking the toxic substances synthesis and metabolism in tobacco leaves or other herbal plants.

APPLICATION OF ADHESIVES AND PLASMA MODIFICATION TO INCREASE THE ADHESIVE STRENGTH OF FIBROUS COMPOSITES

It is shown that the use of amino aldehyde oligomers as an adhesive in fibrous composite materials based on synthetic fibers leads to an increase in the adhesive interaction between components. Due to the limited wettability of the synthetic fiber filler with adhesives, it is advisable to carry out preliminary RF plasma treatment of fibers in a plasma-forming air medium. The matrix polymer and the adhesive have good mutual adhesion, and the lack of adhesion between the adhesive and the synthetic fibers is compensated by the formation of functional reactive groups on the surface of the synthetic fibers during RF plasma treatment.

Immobilization of cellulase on monolith supported with Zr(IV)-based metal-organic framework as chiral stationary phase for enantioseparation of five basic drugs in capillary electrochromatography.

Metal-organic framework (UiO-66-NH2)-incorporated organic polymer monolith was prepared by thermal polymerization. By virtue of the superior physical and chemical properties, the UiO-66-NH2-modified organic monolith was then functionalized by chiral selector cellulase via the condensation reaction between the primary amino groups and aldehyde groups. The synthesized materials were characterized by Fourier transform infrared spectroscopy, high-resolution transmission electron microscopy, scanning electron microscopy, X-ray photoelectron spectrometry, thermogravimetric analysis, and nitrogen sorption isotherm. The cellulase@poly(glycidyl methacrylate-UiO-66-NH2-ethylene glycol dimethacrylate) (cellulase@poly(GMA-UiO-66-NH2-EDMA)) monolith was applied to enantiomerically separate the basic racemic forms of metoprolol, atenolol, esmolol, bisoprolol, and propranolol. In contrast to the cellulase@poly(GMA-co-EDMA) monolith without UiO-66-NH2, the cellulase@poly(GMA-UiO-66-NH2-EDMA) monolith reveals significantly improved enantiodiscrimination performance for metoprolol (Rs: 0 → 1.67), atenolol (Rs: 0 → 1.50), esmolol (Rs: 0 → 1.52), bisoprolol (Rs: 0 → 0.36), and propranolol (Rs: 0 → 0.44). The immobilization pH of cellulase, buffer pH, UiO-66-NH2 concentration, and the proportion of organic modifier were evaluated in detail with enantiomerically separating chiral molecules. The intra-day, inter-day, column-to-column, and inter-batch precision have been discussed, the result was preferable, and the relative standard deviation (RSD) of separation parameters was <4.3%. Schematic representation of the preparation of a UiO-66-NH2-modified organic polymer monolith for enantioseparating five racemic β-blockers. UiO-66-NH2 was synthesized and converted into a monolith as the stationary phase. Then, the modified monolith containing cellulase as the chiral selector was applied in a capillary electrochromatography system for enantioseparating chiral drugs.

Phosphinotripeptidic Inhibitors of Leucylaminopeptidases.

Phosphinate pseudopeptide are analogs of peptides containing phosphinate moiety in a place of the amide bond. Due to this, the organophosphorus fragment resembles the tetrahedral transition state of the amide bond hydrolysis. Additionally, it is also capable of coordinating metal ions, for example, zinc or magnesium ions. These two properties of phosphinate pseudopeptides make them an ideal candidate for metal-related protease inhibitors. This research investigates the influence of additional residue in the P2 position on the inhibitory properties of phosphinopeptides. The synthetic strategy is proposed, based on retrosynthetic analysis. The N-C-P bond formation in the desired compounds is conveniently available from the three-component condensation of appropriate amino components, aldehydes, and hypophosphorous acid. One of the crucial synthetic steps is the careful selection of the protecting groups for all the functionals. Determination of the inhibitor activity of the obtained compounds has been done using UV-Vis spectroscopy and standard substrate L-Leu-p-nitroanilide toward the enzymes isolated from the porcine kidney (SsLAP, Sus scrofa Leucine aminopeptidase) and barley seeds (HvLAP, Hordeum vulgare Leucine aminopeptidase). An efficient procedure for the preparation of phosphinotripeptides has been performed. Activity test shown that introduction of additional residue into P2 position obtains the micromolar range inhibitors of SsLAP and HvLAP. Moreover, careful selection of the residue in the P2 position should improve its selectivity toward mammalian and plant leucyl aminopeptidases.

Targeted urine metabolomics with a graphical reporting tool for rapid diagnosis of inborn errors of metabolism.

The current diagnostic work‐up of inborn errors of metabolism (IEM) is rapidly moving toward integrative analytical approaches. We aimed to develop an innovative, targeted urine metabolomics (TUM) screening procedure to accelerate the diagnosis of patients with IEM. Urinary samples, spiked with three stable isotope‐labeled internal standards, were analyzed for 258 diagnostic metabolites with an ultra‐high performance liquid chromatography‐quadrupole time‐of‐flight mass spectrometry (UHPLC‐QTOF‐MS) configuration run in positive and negative ESI modes. The software automatically annotated peaks, corrected for peak overloading, and reported peak quality and shifting. Robustness and reproducibility were satisfactory for most metabolites. Z‐scores were calculated against four age‐group‐matched control cohorts. Disease phenotypes were scored based on database metabolite matching. Graphical reports comprised a needle plot, annotating abnormal metabolites, and a heatmap showing the prioritized disease phenotypes. In the clinical validation, we analyzed samples of 289 patients covering 78 OMIM phenotypes from 12 of the 15 society for the study of inborn errors of metabolism (SSIEM) disease groups. The disease groups include disorders in the metabolism of amino acids, fatty acids, ketones, purines and pyrimidines, carbohydrates, porphyrias, neurotransmitters, vitamins, cofactors, and creatine. The reporting tool easily and correctly diagnosed most samples. Even subtle aberrant metabolite patterns as seen in mild multiple acyl‐CoA dehydrogenase deficiency (GAII) and maple syrup urine disease (MSUD) were correctly called without difficulty. Others, like creatine transporter deficiency, are illustrative of IEM that remain difficult to diagnose. We present TUM as a powerful diagnostic screening tool that merges most urinary diagnostic assays expediting the diagnostics for patients suspected of an IEM.

Metabolic Modulation of Cardiac Health: The Role of Glucose and Amino Acids

The heart has high metabolic flexibility in utilizing a variety of substrates for energy production. Reprogramming of cardiac metabolism is recognized as integral to the development of heart failure. In hypertrophied and failing hearts, fatty acid oxidation is reduced and glucose utilization is increased. Recent studies have also identified changes in the catabolism of amino acids and ketone bodies in the failing hearts. Thus, elucidating the functional consequence of the metabolic remodeling could provide mechanistic insights of pathogenesis and therapy of heart failure. While the switch from fatty acids to glucose has been shown ultimately maladaptive for energy supply, the impact of increased glucose reliance on cardiac hypertrophy and remodeling is incompletely understood. Emerging results suggest that changes in glucose and amino acid metabolism, apart from their contribution to energy production, serve multiple roles in controlling the hypertrophic growth of the heart. This presentation will focus on the role of substrate metabolism in signal transduction and biosynthetic function of the cardiomyocytes undergoing hypertrophic growth.

Synthesis of β-Hydroxy-α,α-difluorosulfonamides from Carbanions of Difluoromethanesulfonamides

The synthesis of β-hydroxy-α,α-difluorosulfonamides was achieved by reacting difluoromethanesulfonamides with KHMDS in the presence of an aldehyde or ketone. The reaction exhibited a dramatic counterion effect with KHMDS or NaHMDS usually giving excellent yields in minutes, while lithium bases gave little or no product. Excellent yields and high diastereomeric ratios were achieved with Nα-benzyl-Nα-phenylfluorenyl (PhF)-protected chiral amino aldehydes derived from amino acids. Following deprotection, a β-hydroxy-α,α-sulfonamide reacted under peptide coupling and Mitsunobu conditions to furnish a peptidomimetic in an excellent overall yield.

Metabolic Signatures of Genetically Elevated Vitamin D Among Chinese: Observational and Mendelian Randomization Study.

Observational studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with favorable serum lipids and related metabolites. However, whether such observations reflect causality remains unclear. We aimed to investigate the causal effect of elevated 25(OH)D with a detailed systemic metabolite profile in Chinese adults. A total of 225 lipid and other metabolites were quantified in 4662 individuals in the China Kadoorie Biobank. Instrumental variable analyses were performed to test the causal associations of plasma 25(OH)D with lipids and metabolites. Higher plasma 25(OH)D was related to favorable lipid profiles in observational analyses. The genetic risk score was robustly correlated with observed 25(OH)D (beta[SE] = 3.54 [0.32]; P < 1 × 10-5, F-statistic = 122.3) and explained 8.4% of the variation in 25(OH)D in the Chinese population. For all individual metabolites, the causal estimates were not significant at the threshold P < 5 × 10-4 (multiple testing corrected). However, a Mendelian randomization (MR) estimate showed that per 1-SD increase in genetically determined 25(OH)D was suggestive of association with decreased levels of cholesterol, lipoprotein particles, and phospholipids within very small very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) (P ≤ 0.05, nominal significance). For amino acids, fatty acids, ketone bodies, glycoprotein acetyls, fatty acids, and other traits, we did not observe any significant causal association. The MR analysis of metabolic data based a population-based cohort suggested a potential causal association of plasma 25(OH)D with cholesterol, lipoprotein particle, phospholipid concentrations, and total lipids within very small VLDL and IDL. Our findings highlight a long-term effect of 25(OH)D levels in maintaining healthy lipid metabolism.

Moderate Red Wine Consumption Increases the Expression of Longevity-Associated Genes in Controlled Human Populations and Extends Lifespan in Drosophila melanogaster.

The beneficial effects of moderate red wine consumption on cardiovascular health are well known. The composition of red wine includes several compounds, such as the phytoestrogen resveratrol, that exert these beneficial effects, although not all the mechanisms by which they act are known. Our aim was to study the effect of red wine consumption on longevity-related genes in controlled human populations, such as cloistered nuns. We found that the expression of catalase, manganese-superoxide dismutase, Sirt1, and p53 was increased in peripheral blood mononuclear cells after 14 days of moderate red wine consumption. This increase was accompanied by an enhanced metabolic wellness: fatty acids, cholesterol, branched chain amino acids (isoleucine and leucine), ketone bodies (acetoacetate), bacterial co-metabolites (trimethylamine), and cellular antioxidants (taurine) contributed to a change in metabolic profile after moderate red wine consumption by the nuns. No serious unwanted side effects were observed. Finally, we tested the effect of moderate red wine consumption on longevity in a controlled animal population, such as D. melanogaster, and found that it increased average life span by 7%. In conclusion, moderate red wine consumption increases the expression of key longevity-related genes and improves metabolic health in humans and increases longevity in flies.

Evaluation of metabolomics behavior of human colon cancer HT29 cell lines treated with ionic liquid graviola fruit pulp extract

Ethnopharmacological relevanceMedicinal plants have been used by indigenous people across the world for centuries to help individuals preserve their wellbeing and cure diseases. Annona muricata L. (Graviola) which is belonging to the Annonaceae family has been traditionally used due to its medicinal abilities including antimicrobial, anti-inflammatory, antioxidant and cancer cell growth inhibition. Graviola is claimed to be a potential antitumor due to its selective cytotoxicity against several cancer cell lines. However, the metabolic mechanism information underlying the anticancer activity remains limited. Aim of the studyThis study aimed to investigate the effect of ionic liquid-Graviola fruit pulp extract (IL-GPE) on the metabolomics behavior of colon cancer (HT29) by using an untargeted GC-TOFMS-based metabolic profiling. Materials and methodsMultivariate data analysis was used to determine the metabolic profiling, and the ingenuity pathway analysis (IPA) was used to predict the altered canonical pathways after treating the HT29 cells with crude IL-GPE and Taxol (positive control). ResultsThe principal components analysis (PCA) identified 44 metabolites with the most reliable factor loading, and the cluster analysis (CA) separated three groups of metabolites: metabolites specific to the non-treated HT29 cells, metabolites specific to the treated HT29 cells with the crude IL-GPE and metabolites specific to Taxol treatment. Pathway analysis of metabolomic profiles revealed an alteration of many metabolic pathways, including amino acid metabolism, aerobic glycolysis, urea cycle and ketone bodies metabolism that contribute to energy metabolism and cancer cell proliferation. ConclusionThe crude IL-GPE can be one of the promising anticancer agents due to its selective inhibition of energy metabolism and cancer cell proliferation.

Discovery and biosynthesis of guanipiperazine from a NRPS-like pathway.

Nonribosomal peptide synthetases (NRPSs) are modular enzymes that use a thiotemplate mechanism to assemble the peptide backbones of structurally diverse and biologically active natural products in bacteria and fungi. Unlike these canonical multi-modular NRPSs, single-module NRPS-like enzymes, which lack the key condensation (C) domain, are rare in bacteria, and have been largely unexplored to date. Here, we report the discovery of a gene cluster (gup) encoding a NRPS-like megasynthetase through genome mining. Heterologous expression of the gup cluster led to the production of two unprecedented alkaloids, guanipiperazines A and B. The NRPS-like enzyme activates two l-tyrosine molecules, reduces them to the corresponding amino aldehydes, and forms an unstable imine product. The subsequent enzymatic reduction affords piperazine, which can be morphed by a P450 monooxygenase into a highly strained compound through C–O bond formation. Further intermolecular oxidative coupling forming the C–C or C–O bond is catalyzed by another P450 enzyme. This work reveals the huge potential of NRPS-like biosynthetic gene clusters in the discovery of novel natural products.

Bio-based, self-adhesive, and self-healing ionogel with excellent mechanical properties for flexible strain sensor.

Bio-based ionogels with versatile properties are highly desired for practical applications. Herein, we designed a novel self-healing, anti-freezing, and self-adhesive ionogel with excellent sensor capability. The ionogel was obtained by cross-linking amino groups (chitosan) and aldehyde groups (dextran oxide) to form Schiff-base bonds in the ionic liquids (EMIMOAc) with TA. Ionogels inherited the superior electrical conductivity of ionic liquids (IG2, 1.1 mS cm−1). Due to the dynamic reaction of Schiff-base bonds, the obtained IG2 possessed self-healing properties (self-healing efficiency = 89%). The presence of TA also provided the ionogel with excellent self-adhesive properties (IG2/TA, adhesive strength to hogskin = 8.05 kPa). Owing to the low freezing point and low vapor pressure of ionic liquids, ionogels were endowed with anti-freeze properties and resistance to solvent volatility. Moreover, the ionogel can act as a strain sensor, and exhibited excellent sensitivity and sensing performance. Our work provided a green and effective method in preparation of the high performance ionogel sensor, which could accommodate future practical industrial applications.

Recent advances in the synthesis of α-amino ketones.

Due to the importance of the amino ketone motif in synthetic and medicinal chemistry, the number of protocols developed in recent years has considerably increased. This review serves to collate and critically evaluate novel methodologies published since 2011 towards this high value synthon. The chapters are divided by the requisite functionality in the starting material, and an emphasis is placed on discussing functional group compatibility and resultant product substitution patterns. Throughout, applications to medicinal targets are highlighted and mechanistic details are presented, and we further provide a short outlook for future development and emerging potential within this area.