Amino Acid Esters Research Articles

Glycine ester ionic liquid as new co‐initiator used in initiating radical and cationic photopolymerization

AbstractIonic liquids using amino acid ester as cations is a new generation of green ionic liquids. It is found for the first time that they can be used as co‐initiators to initiate radical photopolymerization in the presence of commercial type II sensitizer, camphorquinone (CQ) under mild irradiation conditions. To intensively investigate this new function, we synthesized a series of glycine ester ionic liquids by a very simple method, and then evaluated their performance as co‐initiators in radical photopolymerization. The polymerization studies show that their co‐initiation abilities depend strongly on the structures of N‐terminal substituents and ester groups, as well as the type of anion moiety. And the pH values of the formula also have a heavy influence on their performances. More interestingly, when a small amount of hydroxyethyl acrylate (HEA) was added, under irradiation this multicomponent system composed of CQ, ionic liquids when anion moiety is PF6−, BF4− or SbF6−, and HEA, can release H+ to initiate cationic polymerization. These facts demonstrated that the investigated glycine ester ionic liquids can be considered as valid, environmentally friendly alternatives to toxic aromatic amines co‐initiators. Besides, the corresponding photoinitiation mechanism is suggested.

Metabolomic Analysis of Plasma from Breast Cancer Patients Using Ultra-High-Performance Liquid Chromatography Coupled with Mass Spectrometry: An Untargeted Study.

Breast cancer (BC) is one of the leading causes of cancer mortality in women worldwide, and therefore, novel biomarkers for early disease detection are critically needed. We performed herein an untargeted plasma metabolomic profiling of 55 BC patients and 55 healthy controls (HC) using ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS). Pre-processed data revealed 2494 ions in total. Data matrices’ paired t-tests revealed 792 ions (both positive and negative) which presented statistically significant changes (FDR < 0.05) in intensity levels between cases versus controls. Metabolites identified with putative names via MetaboQuest using MS/MS and mass-based approaches included amino acid esters (i.e., N-stearoyl tryptophan, L-arginine ethyl ester), dipeptides (ile-ser, met-his), nitrogenous bases (i.e., uracil derivatives), lipid metabolism-derived molecules (caproleic acid), and exogenous compounds from plants, drugs, or dietary supplements. LASSO regression selected 16 metabolites after several variables (TNM Stage, Grade, smoking status, menopausal status, and race) were adjusted. A predictive conditional logistic regression model on the 16 LASSO selected ions provided a high diagnostic performance with an area-under-the-curve (AUC) value of 0.9729 (95% CI 0.96–0.98) on all 55 samples. This study proves that BC possesses a specific metabolic signature that could be exploited as a novel metabolomics-based approach for BC detection and characterization. Future studies of large-scale cohorts are needed to validate these findings.

One-pot preparation of N-(α-ferrocenylalkyl) substituted amino acid esters under acid-free conditions

The preparation of N-(α-ferrocenylalkyl) amino acid esters under neutral conditions by the reaction of in situ generated (α-ferrocenylalkyl)carbonates with amino acid esters is described. The method allows regioselective one-pot alkylation of a series of amino acid esters at the amino group, as well as diastereoselective preparation of ferrocenylalkyl substituted amino acid esters from (S)-(+)-α-ferrocenylethanol.

Catalytic asymmetric Tsuji-Trost α-benzylation reaction of N-unprotected amino acids and benzyl alcohol derivatives.

Catalytic asymmetric Tsuji–Trost benzylation is a promising strategy for the preparation of chiral benzylic compounds. However, only a few such transformations with both good yields and enantioselectivities have been achieved since this reaction was first reported in 1992, and its use in current organic synthesis is restricted. In this work, we use N-unprotected amino acid esters as nucleophiles in reactions with benzyl alcohol derivatives. A ternary catalyst comprising a chiral aldehyde, a palladium species, and a Lewis acid is used to promote the reaction. Both mono- and polycyclic benzyl alcohols are excellent benzylation reagents. Various unnatural optically active α-benzyl amino acids are produced in good-to-excellent yields and with good-to-excellent enantioselectivities. This catalytic asymmetric method is used for the formal synthesis of two somatostatin mimetics and the proposed structure of natural product hypoestestatin 1. A mechanism that plausibly explains the stereoselective control is proposed.

Current Drifts in Design and Development of Prodrugs

The design and development of prodrug is based on the objectivity to improve the pharmacokinetic and pharmacodynamic profiles including toxicity of the potent chemical entity. Currently, the prodrug approach is extended with conjugating the parent drug with a self immolating molecule or linker which itself assembles into nanoparticles and prolonged the blood circulation and having passive targeting ability. It also includes delivery of the drug at target site having specific pH condition, delivery of drug to brain by endogenous carrier molecule, NQO1 activable prodrug, prodrug with sustained release behavior, receptor targeted, dual action prodrug, activation via specific enzyme like human carboxylesterase, and phospholipase A2. Some other approaches to prodrug development are that the conversion of active pharmaceutical ingredient (API) into ionic liquids (ILs). In this the biocompatible ionic liquids include choline and amino acid esters are used. One of the anticancer drug methotrexate is formulated into ionic liquid form and used as potential anticancer prodrug. In addition to improvement in combination chemotherapy, there is photoresponsive hybrid prodrug that consists of a photoremovable protecting group. The release of doxorubicin and combrestatin A4 is mainly triggered by 405 nm light and 365 nm light respectively and displayed a quasi-sequential release behavior.

Synthesis and Pharmacological Evaluation of Promising Coumarin Methyl Ester/ Di/Tri/Tetra Peptide Derivatives

Coumarin is a phenol, consisting of benzene ring and alpha-pyrone ring. Coumarins are prepared through Pechmann reaction, which involve condensation of phenol with ethyl acetoacetate in the presence of acid catalyst. Coumarins are being used widely due to their various biological activities in recent years, like anticoagulant, antibacterial, antitumoral, antitubercular, antifungal, MAO inhibitor activity, antioxidant, anti-inflammatory and as CNS active compounds. Methyl esters of amino acids and their di/tri and tetrapeptides derivatives were prepared using coupling agent DCC and a base NMM by stirring continuously for 36 hours. The compounds prepared were analyzed and the structures are elucidated by TLC, IR and 1H NMR spectral data. They were screened for antibacterial activity against three bacterial species and antifungal activity against one species

Influence of the Type of Amino Acid on the Permeability and Properties of Ibuprofenates of Isopropyl Amino Acid Esters.

Modifications of (RS)-2-[4-(2-methylpropyl)phenyl] propanoic acid with amino acid isopropyl esters were synthesised using different methods via a common intermediate. The main reaction was the esterification of the carboxyl group of amino acids with isopropanol and chlorination of the amino group of the amino acid, followed by an exchange or neutralisation reaction and protonation. All of the proposed methods were very efficient, and the compounds obtained have great potential to be more effective drugs with increased skin permeability compared with ibuprofen. In addition, it was shown how the introduction of a modification in the form of an ion pair affects the properties of the obtained compound.

Rhodium(I) carbonyl complexes containing amino acid ester ligands: synthesis, reactivity and DFT studies

Bridge-splitting reaction of the dimer [Rh(CO)2Cl]2 with two molar equivalents of amino acid ester ligands yield the rhodium(I) dicarbonyl complex [Rh(CO)2ClL] (1a-g) {L = glycine methylester (a), alanine methylester (b), alanine ethylester (c), alanine t-butylester (d), phenylalanine methylester (e), phenylalanine ethylester (f), valine methylester (g)}. Complexes 1 undergo oxidative addition (OA) with CH3I to give the five-coordinate Rh(III) complexes of the type [Rh(CO)(COCH3)IClL] (2a–g). The complexes have been characterized by elemental analysis, IR and 1H NMR spectroscopy. Theoretical calculations reveal that the synthesized complexes 1 are very prone to undergo oxidative addition with CH3I with a low activation barrier.

Chiral Recognition of Amino Acid Esters in Organic Solvents Using a Glucose-Based Receptor.

Due to the chemical and biological relevance of amino acids, efficient methods for the recognition and separation of their enantiomers are highly sought after. Chiral receptors based on extended molecular scaffolds are typically employed for this purpose. These receptors are often effective only in specific environments and towards a narrow scope of amino acid guests. Recently we reported a simple, glucose-based macrocycle capable of enantioselective binding of a broad range of amino acid methyl esters in water. Herein we demonstrate that the same receptor can be used for chiral recognition of amino acid esters in organic solvents. We show that the binding affinity and selectivity of the receptor are highly dependent on the coordinating strength of the solvent. An in-depth analysis of the receptor’s conformation and its interactions with amino acid methyl esters allowed us to propose a binding mode of amino acids to the receptor in CDCl3. The binding modes in CDCl3 and D2O were then compared, highlighting the main interactions responsible for binding affinity and selectivity in each solvent. We envision that the insight provided by this study will facilitate the development of further amino acid receptors based on monosaccharides with improved binding affinities and both enantio- as well as chemoselectivities.

Study on the selectivity and phloem mobility of Fenoxaprop-P amino acid ester conjugates on rice and barnyard grass

To improve the selectivity of the fenoxaprop herbicide to rice and barnyard grass, a series of fenoxaprop-P-ethyl-amino acid ester conjugates were designed and synthesized, and tested for biological activity as well as their phloem mobility. The bioassay results indicated that the target compounds possessed better activity against barnyard grass (Echinochloa crusgalli) than rape (Brassica campestris L.) at the concentration of 0.5 mmol/L. Compounds 3h and 3i, showed more than 70% control efficiency against barnyard grass, while less than 30% for rape. The compounds showed less impact on rice after spray treatment than in the germination test. Compounds 3i, 3j, and 3k showed excellently herbicidal activities against barnyard grass and low phytotoxicity to rice. Compound 3k showed 6.1% phytotoxicity to rice at a spray concentration of 0.25 mmol/L, better than fenoxaprop-P-ethyl (61.6%) at the same concentration. The selectivity results of the target compounds revealed that most of compounds obviously reduced phytotoxicity to rice while retaining herbicidal activity of barnyard grass. The herbicidal activity of compound 3d compared to FPE was increased by 50%, while its safety on rice was also increased by 50%. The concentration of the compounds in barnyard grass roots was higher than in rice roots, showing greater phloem mobility. In particular, the concentration of compound 3d on barnyard grass exhibited 142.72 mg/kg which was 3 times as much as Fenoxaprop, while its concentration on rice exhibited 3.65 mg/kg, the results revealed that the difference of phloem mobility might be the important reason for causing the selectivity.

On the Asymmetric Iridium‐Catalyzed N‐Allylation of Amino Acid Esters: Improved Selectivities through Structural Variation of the Chiral Phosphoramidite Ligand

AbstractThe investigation of the iridium‐catalyzed asymmetric N‐allylation of tert‐butyl glycinate using a “branched” racemic 1‐vinyl‐alkyl methyl carbonate revealed severe limitations of existing protocols. By screening a set of 24 BINOL‐derived chiral phosphoramidites a new superior ligand (L24*) was identified which afforded the amination product with high enantioselectivity (≥95 % ee) under optimized conditions. This ligand also allowed the N‐allylation of other amino acid tert‐butyl esters (derived from alanine, phenylalanine, or proline) with outstanding levels of diastereocontrol (d.r. ≥99 : 1) and negligible matched/mismatched differences.

Combustion Synthesis of Nano Fe2O3 and its Utilization as a Catalyst for the Synthesis of Nα-Protected Acyl Thioureas and Study of Anti-bacterial Activities.

A simple and eco-friendly nano Fe2O3 heterogeneous catalytic system is described for the synthesis of acyl thiourea derivatives from corresponding in situ generated acyl isothiocyanates and amino acid esters in acetone obtained in good yields. The structures of synthesized acyl thioureas were confimed by 1H NMR, 13C NMR, mass, and FTIR analysis. Fe2O3 NPs has been prepared via a solution combustion route using ascorbic acid as the reducing agent and ferric nitrate as the source of iron. The prepared nano material has been characterized by XRD, SEM, UV-Visible, and FTIR analysis. More prominently, the Fe2O3 and other impurities are removed though a simple work-up and the material prepared shows to be effective in catalyzing the conversion of reactants to products in good yields. Further, some of the synthesized acyl thioureas were evaluated for in vitro antibacterial activity against Staphylococcus aureus and Escherichia coli.

Total Synthesis and Structure Correction of the Cyclic Lipodepsipeptide Orfamide A.

A total synthesis of the cyclic lipodepsipeptide natural product orfamide A was achieved. By developing a synthesis format using an aminoacid ester building block and SPPS protocol adaptation, a focused library of target compounds was obtained, in high yield and purity. Spectral and LC‐HRMS data of all library members with the isolated natural product identified the 5Leu residue to be d‐ and the 3’‐OH group to be R‐configured. The structural correction of orfamide A by chemical synthesis and analysis was confirmed by biological activity comparison in Chlamydomonas reinhardtii, which indicated compound configuration to be important for bioactivity. Acute toxicity was also found against Trypanosoma brucei, the parasite causing African sleeping sickness.

Amine Transaminase Mediated Synthesis of Optically Pure Piperazinones and 1,4‐Diazepanones

AbstractA biocatalytic approach has been designed for the synthesis of optically active piperazinones and 1,4‐diazepanones in aqueous medium under mild conditions. The method described herein is based on a biocatalytic transamination of an easily accessible N‐(2‐oxopropyl) amino acid ester and the subsequent spontaneous cyclization of the initially formed amine. Both enantiomers of the synthesized piperazinones can be prepared by the selection of amine transaminases of opposite selectivity. The reaction conditions were optimised and eight selected processes were performed on a preparative scale. Thus, seven optically active piperazinones were synthesized in high isolated yields (70–90%) and a 1,4‐diazepanone in a moderate yield (51%), being the ee ≥99% in all the cases.magnified image

Design, Synthesis and Biological Evaluation of Prodrugs of 666-15 as Inhibitors of CREB-Mediated Gene Transcription.

cAMP-response element binding protein (CREB) is a transcription factor involved in multiple cancers. Chemical inhibitors of CREB represent potential anticancer agents. We previously identified 666-15 as a potent CREB inhibitor. While 666-15 showed efficacious anticancer activity in vivo through intraperitoneal (IP) injection, its oral bioavailability is limited. To increase its oral bioavailability, we describe synthesis and evaluation of prodrugs based on 666-15. The amino acid esters were attempted, but they were not stable for detailed characterization. The corresponding sulfate and phosphates were prepared. The sulfate of 666-15 was too stable to release 666-15 while the phosphates were converted into 666-15 with half-lives of ∼2 h. Phosphate 3 was also a potent CREB inhibitor with anti-breast cancer activity. Furthermore, compound 3 showed much improved oral bioavailability at 38%. These studies support that 3 can be used as an oral CREB inhibitor while IP administration of 666-15 is preferred for in vivo applications.

Convenient Approach to Bicyclic Sultams

AbstractA method for the synthesis of aminomethyl-substituted five-membered sultams has been developed. The aminomethyl sultams were synthesized from the corresponding iodomethyl derivatives by nucleophilic substitution of the iodine atom with sodium azide followed by reduction on Pd/C. This method was further expanded to side-chain-substituted sultams, starting from amino acid esters, to obtain aminomethyl-containing bicycles. The simple practical procedure and available starting amino acid esters, including chiral examples, make various bicyclic sultams readily available.

Coumarins inhibit η-class carbonic anhydrase from Plasmodium falciparum

Coumarins were discovered to act as inhibitors of α-carbonic anhydrases (CAs, EC 4.2.1.1) after undergoing hydrolysis mediated by the esterase activity of the enzyme to the corresponding 2-hydroxycinnamic acids. Other classes of CAs among the eight currently known do not possess esterase activity or this activity was poorly investigated. Hence, we decided to look at the potential of coumarins as inhibitors of the η-CA from the malaria-producing protozoan Plasmodium falciparum, PfaCA. A panel of simple coumarins incorporating hydroxyl, amino, ketone or carboxylic acid ester moieties in various positions of the ring system acted as low to medium micromolar PfaCA inhibitors, whereas their affinities for the cytosolic off-target human isoforms hCA I and II were in a much higher range. Thus, we confirm that η-CAs possess esterase activity and that coumarins effectively inhibit this enzyme. Elaboration of the simple coumarin scaffolds investigated here may probably lead to more effective PfaCA inhibitors.

Synthesis and characterisation of phenanthroline-oxazine ligands and their Ag(I), Mn(II) and Cu(II) complexes and their evaluation as antibacterial agents.

A series of phenanthroline-oxazine ligands were formed by a cyclisation reaction between L-tyrosine amino acid esters and 1,10-phenanthroline-5,6-dione (phendione). The methyl derivative of the phenanthroline-oxazine ligand 1 was complexed with Ag(I), Mn(II) and Cu(II) to form [Ag(1)2]ClO4, [Mn(1)3](ClO4)2 and [Cu(1)3](ClO4)2. The activity of these metal complexes was tested against the bacteria Escherichia coli and Staphylococcus aureus. Each of the metal complexes was more active than1 against S. aureus and the Mn(II) and Cu(II) complexes also showed greater activity than 1 towards E. coli. The effect of increasing the length of the alkyl moiety on the phenanthroline-oxazine ligands and their corresponding tris homoleptic Cu(II) complexes was investigated. In all cases both the ligands and their complexes were more active against Gram-positive S. aureus than against Gram-negative E. coli. Differences in the lipophilicity of the ligands and their corresponding Cu(II) complexes did alter the antibacterial activity, with the hexyl and octyl derivatives and their complexes showing the greatest activity and comparing well with clinically used antibiotics. The most active Cu(II) complexes and their respective ligands were also active against Methicillin-resistant S. aureus (MRSA). In vivo toxicity studies, conducted using the Galleria mellonella model, showed that all of the compounds were well tolerated by the insect larvae.

Coumarins effectively inhibit bacterial α-carbonic anhydrases

Coumarins are known to act as prodrug inhibitors of mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) but they were not yet investigated for the inhibition of bacterial α-CAs. Here we demonstrate that such enzymes from the bacterial pathogens Neisseria gonorrhoeae (NgCAα) and Vibrio cholerae (VchCAα) are inhibited by a panel of simple coumarins incorporating hydroxyl, amino, ketone or carboxylic acid ester moieties in various positions of the ring system. The nature and the position of the substituents in the coumarin ring were the factors which strongly influenced inhibitory efficacy. NgCAα was inhibited with KIs in the range of 28.6–469.5 µM, whereas VchCAα with KIs in the range of 39.8–438.7 µM. The two human (h)CA isoforms included for comparison reason in the study, hCA I and II, were less prone to inhibition by these compounds, with KIs of 137–948.9 µM for hCA I and of 296.5–961.2 µM for hCA II, respectively. These findings are relevant for discovering coumarin bacterial CA inhibitors with selectivity for the bacterial over human isoform, with potential applications as novel antibacterial agents.

Vinca Hybrids with Antiproliferative Effect

Vinca alkaloids used in anticancer therapy are the well-known vinblastine and vincristine as classical antitumor agents. These dimeric molecules consist of two monomers, vindoline and catharanthine, which have no particular activity on their own. The goal in our research work was to obtain derivatives of one of these, vindoline, resulted in molecules with important antiproliferative effect. This type of derivatives were hybrids; vindoline was conjugated with several pharmacophores with and/or without linkers. Pharmacophores were amino acid esters, steroids, triazoles, and flavones. In several cases, the synthesized compounds showed on some cell lines an even better effect than vinblastine.