Glycine Derivatives Research Articles

Dietary Betaine Attenuates Obesity: Involvement of Hepatic MicroRNAs

Obesity affects more than one people in three and reduces life expectancy by 5–20 years globally. Dietary intervention is a preferred strategy for prevention and treatment of obesity. Betaine is a derivative of glycine widely distributed in food, and it functions as a methyl donor and osmolyte. Recent studies revealed betaine as a metabolism modulator, but the underlying mechanisms are largely unknown. In this study, high energy diet-induced obesity mice were administrated with betaine at 120 mg/kg bodyweight daily by gavage for 4 weeks. By histology, biochemistry and hormones analysis, dietary betaine was revealed to attenuate obesity by normalizing glucose and lipid metabolism significantly. Subsequently, the hepatic microRNA expression was determined by real-time PCR. It was found that betaine treatment reversed the elevated miR-27a, miR-27b, miR-34a, miR-200b and miR-223 in obese mice. These data confirmed the anti-obesity effect of dietary betaine and provided a novel perspective for understanding its underlying mechanisms.

Visible‐Light‐Induced Oxidative α‐Alkylation of Glycine Derivatives with Ethers under Metal‐Free Conditions

AbstractIn this work, a visible‐light‐induced oxidative α‐alkylation of glycine derivatives with ethers has been developed in the presence of catalytic Eosin Y. Under the blue light of a 3 W LED, a range of α‐etherized glycine derivatives, including α‐amino esters, α‐amino ketones and α‐amino amides, were achieved with good to excellent yields and functional group tolerance with tert‐butyl hydroperoxide (TBHP) as oxidant at ambient temperature. The operationally easy procedure provides an economical, metal‐free, and mild alternative for the synthesis of the α‐etherized glycine derivatives.

Single Electron Transfer‐Induced Selective α‐Oxygenation of Glycine Derivatives

AbstractModification of amino acids is an important strategy in organic and bioorganic chemistry. In contrast to common side‐chain functionalization, backbone modification is much less explored. Especially glycine units seem to be attractive and versatile since a wide range of functionality can be potentially introduced. We report here oxidative modification of glycinates that are stable and enable further functionalization. Selective glycinate enolate oxidation by TEMPO or a FeCp2PF6/TEMPO reagent combination provides stable alkoxyamines in good to excellent yields. The methodology is expanded to glycine‐containing dipeptides demonstrating selective oxygenation at the glycine unit. The orthogonal reactivity potential of oxygenated glycines for transformation to other amino acid derivatives is explored.magnified image

Human metabolism and urinary excretion of seven neonicotinoids and neonicotinoid-like compounds after controlled oral dosages

Few human data on exposure and toxicity are available on neonicotinoids and neonicotinoid-like compounds (NNIs), an important group of insecticides worldwide. Specifically, exposure assessment of humans by biomonitoring remains a challenge due to the lack of appropriate biomarkers. We investigated the human metabolism and metabolite excretion in urine of acetamiprid (ACE), clothianidin (CLO), flupyradifurone (FLUP), imidacloprid (IMI), sulfoxaflor (SULF), thiacloprid (THIAC) and thiamethoxam (THIAM) after single oral dosages at the currently acceptable daily intake levels of the European Food Safety Authority. Consecutive post-dose urine samples were collected up to 48 h. Suspect screening of tentative metabolites was carried out by liquid chromatography–high-resolution mass spectrometry. Screening hits were identified based on their accurate mass, isotope signal masses and ratios, product ion spectra, and excretion kinetics. We found, with the exception of SULF, extensive metabolization of NNIs to specific metabolites which were excreted next to the parent compounds. Overall, 24 metabolites were detected with signal intensities indicative of high metabolic relevance. Phase-I metabolites were predominantly derived by mono-oxidation (such as hydroxy-FLUP, -IMI, and -THIAC) and by oxidative N-desalkylation (such as N-desdifluoroethyl-FLUP and N-desmethyl-ACE, -CLO and -THIAM). IMI-olefin, obtained by dehydration of hydroxylated IMI, was identified as a major metabolite of IMI. SULF was excreted unchanged in urine. Previously reported metabolites of NNIs such as 6-chloronicotinic acid or 2-chlorothiazole-4-carboxylic acid and their glycine derivatives were detected either at low signal intensities or not at all and seem less relevant for human biomonitoring. Our highly controlled approach provides specific insight into the human metabolism of NNIs and suggests suitable biomarkers for future exposure assessment at environmentally relevant exposures.

Photocatalyzed Reverse Polarity Oxidative Povarov Reaction of Glycine Derivatives with Maleimides

Main observation and conclusionAn oxidative tandem (4+2)‐cyclization/aromatization of N‐aryl glycine derivatives with electron‐deficient alkenes was first achieved using Ru(bpy)3Cl2 as a photocatalyst and TBHP as an oxidant in combination with visible‐light irradiation by blue LEDs. One‐electron oxidation and the following α‐deprotonation of glycine derivatives afford α‐amino alkyl radicals, which were then trapped by electrophilic maleimides. As an atom‐economic and efficient method, a variety of pyrrolo[3,4‐c]quinoline‐1,3‐diones have been obtained in good yields under mild reaction conditions.

Mechanism of action and the uses betaine in pig production.

Betaine, the trimethyl derivative of glycine, is a good methyl group donor, and an important component in pig production. However, betaine has not been extensively studied in this field. Therefore, in this study, we reviewed the effects of betaine in pig production performance, meat quality and reproductive performance, as well as its mechanisms, to provide a theoretical basis for the optimal use and development of this compound.

Carcinogenic evaluation of the herbicide glyphosate

Glyphosate, an herbicidal derivative of the amino acid glycine, was introduced to agriculture in the 1970s. Glyphosate is widely considered by regulatory authorities and scientific bodies to have no carcinogenic potential. These have been also reviewed by numerous regulatory agencies including the US Environmental Protection Agency, the European Commission, and the Canadian Pest Management Regulatory Agency; however, The International Agency for Research on Cancer (IARC) published a monograph in 2015 concluding that glyphosate is “probably carcinogenic to humans”. In this review, we evaluated the carcinogenicity of the herbicide glyphosate, based on analyses of case control or cohort epidemiology studies that determinate the association between glyphosate and cancer. There are fourteen case-control studies; the assessment found that the data do not support a causal relationship between glyphosate exposure and cancer. As a result, the Panels concluded that glyphosate is unlikely to pose a carcinogenic risk to humans. Despite this results, future studies could be improved by more careful attention to validating exposure to glyphosate, thus we need for research on the health effects of glyphosate-based herbicides.

Visible-Light-Driven Redox Neutral Direct C-H Amination of Glycine Derivatives and Peptides with N-Acyloxyphthalimides.

A room temperature, visible-light-promoted and redox neutral direct C-H amination of glycine and peptides has been firstly accomplished by using N-acyloxyphthalimide or -succinimide as nitrogen-radical precursor. The present strategy provides ways to introduce functionalities such as N-acyloxyphthalimide or -succinimide specifically to terminal glycine segment of peptides. Herein, mild conditions and high functional-group tolerance allow the preparation of non-natural α-amino acids and modification of corresponding peptides in this way.

Silyl-protected propargyl glycine for multiple labeling of peptides by chemoselective silyl-deprotection

We synthesized Fmoc-propargyl glycine derivatives bearing different silyl protecting groups that can be readily introduced by using a standard solid-phase peptide coupling procedures. Taking advantage of the orthogonality between the different silyl protecting groups, chemoselective incorporation of functional molecules into a 19-mer peptide through click reactions was demonstrated.

Visible‐Light‐Induced Aerobic Oxidative Csp3−H Functionalization of Glycine Derivatives for 2‐Substituted Benzoxazoles

AbstractWe report a simple oxidative Csp3−H functionalization reaction of glycine derivatives by visible‐light photoredox catalysis. A wide range of glycine derivatives readily undergo the oxidative cyclization to afford various 2‐substituted benzoxazoles. Importantly, this photocatalytic intramolecular dehydrogenative coupling reaction allows for the C−H functionalization of glycine derivatives involving short peptides under mild conditions, which may have value in preparing peptide‐derived pharmacologically active molecules.magnified image

Iron-Catalyzed Cyanoalkylation of Glycine Derivatives Promoted by Pyridine-Oxazoline Ligands

An iron-catalyzed C(sp3)–H cyanoalkylation of glycine derivatives with cyclobutanone oxime esters was established for the incorporation of a cyano group into amino acids and peptides. In this reaction, Fe(NTf2)2 and pyridine-oxazoline ligands form highly active catalysts that could simultaneously and selectively activate both substrates. Preliminary mechanistic studies revealed the excellent chemo-selectivity may stem from an in situ formed imine intermediate and a consecutive radical addition. The evidence suggested the interaction between glycinate substrate and the Fe-catalyst has a prominent impact on the catalytic activity, and the catalyst may also activate the imine intermediate as a Lewis acid.

Structural engineering in pre-functionalized, imine-based covalent organic framework via anchoring active Ru(II)-complex for visible-light triggered and aerobic cross-coupling of α-amino esters with indoles

Site-specific functionalization of sp3 CH bonds adjacent to a nitrogen atom is one of the unexplored heterogeneous transformations. Aiming at α-arylation of glycine derivative for rapid access to indolylglycines without the aid of bases, a chemically robust and two-dimensional COF is prepared. Integration of [2,2′]bipyridyl (Bpy) unit benefits active homogeneous complex Ru(Bpy)22+ to anchor over the framework backbone to devise Ru-COF that acts as unprecedented visible light photocatalyst towards cross-dehydrogenative coupling of secondary amines with indoles in excellent yield at room temperature, under aerobic condition. Ru-COF shows admirable reusability and superior activity to that of Ru(Bpy)3Cl2, while substrate variation studies delineate wide ranges of functional group tolerance. To the best of Ru-COF, atom-economic CH functionalization is realized as iminium ion is in situ generated. The photocatalytic route is detailed from astute modulation of optical band-gap in light of density-functional theory studies and experimental results, which validates single-electron-transfer pathway.

Observation of Conformational Simplification upon N-Methylation on Amino Acid Iodide Clusters.

This Letter reports a counterintuitive observation that methylation of the glycine-iodide cluster leads to fewer conformations and spectroscopic simplicity. Cryogenic "iodide-tagging" negative ion photoelectron spectroscopy (NIPES) is used to probe specific binding sites of three N-methylated glycine derivatives, i.e., N-methylglycine (sarcosine), N,N-dimethylglycine, and N,N,N-trimethylglycine (glycine betaine). NIPES reveals a progressive spectral simplification of the iodide clusters with increasing methylation due to fewer contributing structures. Low energy conformers and tautomers of each cluster are computationally identified, and those observed in the experiments are assigned based on excellent agreement between the NIPE spectra and theoretical simulations. Zwitterionic cluster structures are found to be less stable than their canonical forms and do not contribute to the observed spectra. This work demonstrates the power of iodide-tagging NIPES in probing conformations of amino acid-iodide clusters and provides a molecular level understanding on the effect of methyl substitution on amino acid binding sites.

Dietary supplementation with betaine or glycine improves the carcass trait, meat quality and lipid metabolism of finishing mini-pigs.

The objective of the study is to evaluate and compare the effects of betaine or glycine on carcass trait, meat quality and lipid metabolism of finishing Huan Jiang mini-pigs. Betaine called trimethylglycine is a methyl derivative of glycine, but few researches were conducted to compare the impact of dietary betaine and glycine on pigs. One hundred and forty-four Huan Jiang mini-pigs (body weight = 10.55 ± 0.15 kg; 70 d) were randomly divided to 3 treatment groups (basal diet, glycine or betaine). Results indicated that dietary betaine increased the average daily gain (ADG) and final weight (P < 0.05). Dietary glycine or betaine markedly reduced average backfat thickness (P < 0.05) and heightened lean percentage (P < 0.01) compared to the control group. Moreover, in comparison with the control group, betaine significantly improved the redness (a∗) and tenderness (shear force) of the longissimus dorsi (LD) muscle (P < 0.05), whereas glycine only raised the value of a∗ of the LD muscle (P < 0.05). These results showed that diet supplemented with 0.25% betaine and equimolar amounts of glycine could regulate cascass trait and meat quality of finishing Huan Jiang mini-pigs, and the effect of betaine was superior to that of glycine.

Investigating the anticancer properties of the two new platinum complexes with iso- and tert-pentylglycine by the DFT, molecular docking, and ADMET assessment and experimental confirmations.

In this study, two new anticancer platinum complexes formulated as [Pt(bpy)(L)]NO3 were synthesized using the iso and tert-pentylglycine ligands, two structural isomer ligands, to investigate side branches effect on the complex-DNA interaction. According to the comparative results of the ADMET assessment, these compounds can be considered as the drug-like molecules and oral medication. Mechanism of tumor inhibition and DNA binding parameters indicated the higher ability of the tert-isomer and also, both complexes acted through the disruption of the base pairs and stacks of helicity by the endothermic process. Fluorescence spectroscopy showed that the quenching mechanism is static for both drugs with large binding constant and high binding affinity towards the DNA. Also, the amount of binding constant of the tert -isomer was about 14 times of another structural isomerous complex. CD spectra indicated the conversion of the B-DNA into A-DNA form via electrostatic interaction for positively charged complexes. The cytotoxic data showed that both compounds have antiproliferative effects against the MCF-7 cell line and the inhibitory effect of the iso-derivative was better than the tert-one. Docking studies showed that the desolvation energy and hydrogen bond are more effective between the other interactions. The torsional free energy for both complexes mainly provided the groove binding along with partially electrostatic and intercalate binding. According to the density-functional theory data and because of positive electron density on the surface of complexes and facilitating of the metal drug to DNA phosphate groups approaching, both complexes may be good candidates for the anticancer drugs. Two new anticancer Pt(II) complexes were synthesized with glycine derivatives. In vitro cytotoxicity effects were tested against the human breast cancer cell line of MCF-7. Moreover, the modes of DNA binding with synthesized compounds were investigated using ADME prediction, DFT, molecular docking and spectroscopic methods.

Synthesis of Some New N-protected 2-(Substituted-1H-1,2,3-Triazol-1-yl)glycine Derivatives

We report in this paper the synthesis of some new N -protected 2-(substituted-1 H -1,2,3-triazol-1-yl)glycine derivatives through saponification reaction in basic medium. The structures of obtained products were established on the basis of NMR spectroscopy ( 1 H, 13 C), MS data and elemental analysis.

Three anticancer Pt complexes with glycine derivatives: synthesis, bioactivity on MCF-7 cell line, ADME prediction, DFT, MEP, and molecular docking

For investigating reduction of side effects of commercial anticancer drugs, such as cisplatin, three new platinum complexes with glycine derivatives and the formula of [Pt(R-amine)2(R-gly)]NO3 were synthesized where R-amine is propylamine, isopentylamine, and tertpentylamine and R-gly is propylglycine, isopentylglycine, and tertpentylglycine, which were characterized by spectroscopic methods, such as ultraviolet–visible, infrared, and proton nuclear magnetic resonance (1H-NMR) spectroscopy. The in-vitro cytotoxicity of these water-soluble complexes and cisplatin as a controller was assessed against MCF-7 cell line by MTT assay. The 50% inhibitory concentration values showed that the inhibitory effect of propyl derivative was better than the other systems. According to solubility of these compounds in water and also comparing the results of assessing adsorption, distribution, metabolism, and excretion, these compounds can be considered as drug-like molecules and oral medication. Given the density functional theory data, such as electronegativity, nucleophilicity, additional electronic charges, and global softness, anticancer properties of the synthesized complexes were almost similar and predominantly more than the cisplatin. DNA binding modes were evaluated by experimental circular dichroism (CD) spectroscopy, and also theoretical study of molecular docking. CD spectra showed a decrease in the intensity of the positive band and an increase in the negative band indicating formation of DNA-complex electrostatic interaction for positively charged synthesized complexes. CD spectra indicated conversion of B-DNA into A-DNA form via electrostatic interaction for positively charged propyl complex at high concentration. Results of studying molecular docking showed that hydrogen bonding is more effective than other interactions, such as electrostatic and covalent interactions, especially for bulky systems. In this regard, glycine derivatives may reduce the side effects of Pt-drugs in treatment of cancer. Three new anticancer Pt(II) complexes were synthesized with glycine derivatives. In vitro cytotoxicity effects were tested against the human breast cancer cell line of MCF-7. Moreover, the modes of DNA binding with synthesized compounds were investigated using Circular dichroism spectra, ADME prediction, DFT, MEP, and molecular docking.

Photocatalytic decarboxylative alkylations of C(sp3)-H and C(sp2)-H bonds enabled by ammonium iodide in amide solvent

A simple ammonium iodide salt in amide solvent catalyzes regioselective decarboxylative alkylation of C(sp3)-H bonds of N-aryl glycine derivatives, of C(sp2)-H bond of heteroarenes, and cascade radical addition to unsaturated bond followed by intramolecular addition to arene, with a broad scope of N-hydroxyphthalimide derived redox active esters under visible light irradiation. The reactions are suggested to proceed through photoactivation of a transiently assembled chromophore from electron-deficient phthalimide moiety and iodide anion through an anion-π interaction in solvent cage followed by diffusion to generate solvated free radical species to react with C-H substrates The simplicity, practicality, and broad substrate scope of this method highlight the synthetic power of photocatalysis through transiently assembled chromophore, and will hopefully inspire further developments of low cost photocatalysis based on various non-covalent interactions, which are prevalent in supramolecular chemistry and biosystems, for sustainable organic synthesis.

Spontaneous In Vitro and In Vivo Interaction of (-)-Oleocanthal with Glycine in Biological Fluids: Novel Pharmacokinetic Markers.

Since the first discovery of its ibuprofen-like anti-inflammatory activity in 2005, the olive phenolic (-)-oleocanthal gained great scientific interest and popularity due to its reported health benefits. (-)-Oleocanthal is a monophenolic secoiridoid exclusively occurring in extra-virgin olive oil (EVOO). While several groups have investigated oleocanthal pharmacokinetics (PK) and disposition, none was able to detect oleocanthal in biological fluids or identify its PK profile that is essential for translational research studies. Besides, oleocanthal could not be detected following its addition to any fluid containing amino acids or proteins such as plasma or culture media, which could be attributed to its unique structure with two highly reactive aldehyde groups. Here, we demonstrate that oleocanthal spontaneously reacts with amino acids, with high preferential reactivity to glycine compared to other amino acids or proteins, affording two products: an unusual glycine derivative with a tetrahydropyridinium skeleton that is named oleoglycine, and our collective data supported the plausible formation of tyrosol acetate as the second product. Extensive studies were performed to validate and confirm oleocanthal reactivity, which were followed by PK disposition studies in mice, as well as cell culture transport studies to determine the ability of the formed derivatives to cross physiological barriers such as the blood-brain barrier. To the best of our knowledge, we are showing for the first time that (-)-oleocanthal is biochemically transformed to novel products in amino acids/glycine-containing fluids, which were successfully monitored in vitro and in vivo, creating a completely new perspective to understand the well-documented bioactivities of oleocanthal in humans.

Bi-functional gold nanoparticles composites regulated by graphene quantum dots with various surface states

In this work, the graphene quantum dots (GQDsx, x = 1, 2 and 3) with various surface states were synthesized. Subsequently, GQDsx were facially assembled with glycine derivative (G6) and gold nanoparticles (AuNPs), and novel AuNPs/G6/GQDsx composites were achieved. Furthermore, the fluorescence and SERS results showed the strong dependence on the surface state of GQDs excluding the quantum size effects, which demonstrated the close relationship between the energy transfer efficiency of photoexcited GQDsx and AuNPs. In addition, in comparision with the crystal violet (CV)’ SERS response on GQDsx and AuNPs/G6/GQDsx substrate, it was indicated that the electromagnetic fields effect of AuNPs/G6/GQDsx was also closely related to the surafce state of GQDs. Moreover, the synergetic effect of AuNPs with GQDsx was beneficial to improve the SERS response of AuNPs/G6/GQDsx substrate.