Alanine Derivatives Research Articles

A new amino acid, hybrid peptides and BODIPY analogs: synthesis and evaluation of 2-aminotroponyl-L-alanine (ATA) derivatives.

Natural aromatic α-amino acid residues play critical roles in the structural and functional organization of proteins owing to π-interactions. Their aromatic residues are derived from benzenoid scaffolds. Non-benzenoid aromatic scaffolds such as tropone and tropolone are also constituents of troponoid natural products. Tropolone has also the ability to exhibit π-interactions along with additional hydrogen bonding. Thus, amino acids comprising troponyl could be potential building blocks of novel peptidomimetics. This report describes the synthesis of the L-aminotroponylalanine amino acid (ATA) and its unusual activity with the peptide coupling agent EDC. Importantly, its di-peptides form β-sheet/-turn type secondary structures in organic solvents owing to the troponyl residue. This amino acid is an excellent scaffold for the synthesis of fluorescent amino acids such as BODIPY amino acid analogs. Nevertheless, this amino acid and its BODIPY derivatives can enter HeLa cells without exhibiting significant cytotoxicity at low concentrations (∼50 μM). Hence, ATA and its BODIPY derivatives are promising aromatic amino acids for the construction of potential peptidomimetics and fluorescent labelling of target peptides.

Quinine as a highly responsive chiral sensor for the 1H and 19F NMR enantiodiscrimination of N-trifluoroacetyl amino acids with free carboxyl functions.

Hydrogen-bond accepting and enantiodiscriminating abilities of quinine (Qui) have been exploited in the enantiodiscrimination of N-trifluoroacetyl (TFA) derivatives of amino acids by nuclear magnetic resonance (NMR) spectroscopy. 1H and 19F NMR resonances of derivatives of alanine, valine, leucine, norvaline, phenylalanine, phenylglycine, methionine, glutamic acid, proline, and tryptophan were well differentiated employing CDCl3 and/or C6D6 as solvent, with Qui acting in some cases not only as enantiodiscriminating agent, but also as solubility promoter. For derivatives soluble in both solvents, the best results were obtained in benzene-d6, with very high nonequivalence values, which were detectable not only starting from very low equimolar concentrations of 0.1 mM, but also in the presence of sub-stoichiometric amounts of Qui. The quality of enantiodifferentiation has been also evaluated by means of the enantioresolution quotient E. The method has been applied to the detection and quantification of mixtures of amino acid derivatives by single point measurements.

Bis(alaninato)iron(II) complexes as molecular scaffolds for the generation of N,N-di-glycated alanine derivatives in the presence of glucose

Metal ions are known to influence the course of the Maillard reaction through formation of various complexes such as bis(amino acids), these complexes are known to undergo more facile reaction with sugars. Due to this enhanced reactivity, the possible formation of di-glycated amino acids in glucose/alanine model systems with and without FeCl2 was investigated using isotope labelling technique in conjunction with ESI/qTOF/MS/MS. Forty-eight derivatives of bis[N,N'-di-glycated alanine] iron(II) complexes were tentatively identified. These complexes incorporated one iron atom, two [13C-3] atoms from alanine and up-to twenty-four carbon atoms from glucose [13C-U], were incorporated as triose (C3), tetrose (C4), pentose (C5) or hexose (C6) moieties. Furthermore, the dissociation of the above complexes released variously substituted N,N-di-glycated alanine derivatives incorporating one alanine [13C-3] atom and up to twelve carbon atoms from glucose [13C-U]. The MS/MS analysis of diglycated alanines indicated that they follow similar fragmentation pathways as Amadori product of alanine.

Intrinsic anisotropy parameters of a series of lanthanoid complexes deliver new insights into the structure-magnetism relationship

Intrinsic anisotropy parameters of a series of lanthanoid complexes deliver new insights into the structure-magnetism relationship

Organometallic reagents primed for peptide modification

In this issue of Chem Catalysis , Walczak and co-workers introduce a carbastannatrane alanine derivative that facilitates amino acid side-chain functionalizations via C–C, C–S, and C–Se bond formation using Stille cross-coupling reactions. Applications in late-stage peptide modifications and macrocyclizations further exemplify the value of this novel building block. In this issue of Chem Catalysis , Walczak and co-workers introduce a carbastannatrane alanine derivative that facilitates amino acid side-chain functionalizations via C–C, C–S, and C–Se bond formation using Stille cross-coupling reactions. Applications in late-stage peptide modifications and macrocyclizations further exemplify the value of this novel building block.

Biological activity of 3-(2-benzoxazol-5-yl)alanine derivatives

Searching for new drugs is still a challenge for science, mainly because of civilization development and globalization which promote the rapid spread of diseases, which is particularly dangerous in the case of infectious ones. Moreover, readily available already known antibiotics are often overused or misused, possibly contributing to the increase in the number of multidrug-resistant microorganisms. A consequence of this is the need for new structures of potential drugs. One of them is a benzoxazole moiety, a basic skeleton of a group of fluorescent heterocyclic compounds already widely used in chemistry, industry, and medicine, which is also present in naturally occurring biologically active compounds. Moreover, synthetic benzoxazoles are also biologically active. Considering all of that, a large group of non-proteinogenic amino acids based on 3-(2-benzoxazol-5-yl)alanine skeleton was studied in search for new antimicrobial and anticancer agents. Screening tests revealed that antibacterial potential of 41 compounds studied is not very high; however, they are selective acting only against Gram-positive bacteria (B. subtilis). Moreover, almost half of the studied compounds have antifungal properties, also against pathogens (C. albicans). Most of studied compounds are toxic to both normal and cancer cells. However, in a few cases, toxicity to normal cells is much lower than for cancer cells indicating these compounds as future anticancer agents. The research carried out on such a large group of compounds allowed to establish a structure–activity relationship which enables to select candidates for further modifications, necessary to improve their biological activity and obtain a new lead structure with potential for therapeutic use.

Construction of Racemic and Enantiopure Biaryl Unnatural Amino Acid Derivatives via Pd(II)‐Catalyzed Arylation of Unactivated Csp3−H Bonds

AbstractWe report the construction of racemic and enantiopure biaryl unnatural amino acid derivatives via the palladium‐catalyzed stereoselective sp3 C−H activation and arylation of amino acid derivatives with iodobiaryls. The synthesis of biaryl motif installed (DL‐), L‐ and D‐amino acid derivatives including norvaline, phenylalanine, leucine, norleucine and 2‐aminooctanoic acid with anti stereochemistry is reported. The synthesis of alanine derivatives with two biaryl motifs and aminoalkanoic acids with biaryl motifs is also shown. The C−H arylation of enantiopure carboxamides gave biaryl amino acid derivatives with good enantiopurity. Removal of the directing group 8‐aminoquinoline, deprotection of the phthalimide moiety, and the preparation of biaryl amino acid derivatives containing free amino‐ and carboxylate groups are also reported. The stereochemistry (anti) of representative major diastereomers was unequivocally ascertained from X‐ray structure analysis. Biaryl amino acids/peptides are important motifs in medicinal chemistry, and this work therefore represents a contribution towards enriching the library of biaryl amino acids.

Palladium-Catalyzed sp3 C–H Benzoxylation of Alanine Derivatives Using Aldehydes under Ambient Conditions

AbstractThe Pd(II)-catalyzed sp3 C–H bond benzoxylation of N-phthaloylalanine derivatives possessing an 8-aminoquinolyl group as a directing group with aldehydes under ambient conditions is reported. When a solution of an alanine derivative and an aldehyde in a toluene/water co-solvent was reacted in the presence of palladium catalyst and tert-butyl hydroperoxide at room temperature, a benzoxylated product was formed in up to 68% yield. The protecting group of the obtained benzoxylated product was smoothly removed to afford a free amide in high yield.

Triple-Modulated Chiral Inversion of Co-Assembly System Based on Alanine Amphiphile and Cyanostilbene Derivative.

The construction of chiroptical materials with controllable chirality is of special importance in biology and chemistry. Although tunable chirality can be realized in various systems, it remains a fundamental challenge to realize multimodulated chiral inversion. Herein, we report that chiral alanine derivative and fluorescent cyanostilbene derivative co-assemble to prepare supramolecular chiral systems, where twist nanofibers with totally inverted supramolecular chirality and circularly polarized luminescence are obtained through stoichiometric modulation. The supramolecular handedness can be inverted by means of altering the cooling rate and incorporating metal ions. The mechanism study reveals that the synergistic effect among hydrogen bonds, coordination interactions, and π-π stacking interactions contributes to the chirality inversion. This work establishes an effective strategy to precisely modulate supramolecular chirality in multiple ways, which shows great potential in developing smart chiroptical materials capable of achieving complex functionalities.

Peripheral Selective Oxadiazolylphenyl Alanine Derivatives as Tryptophan Hydroxylase 1 Inhibitors for Obesity and Fatty Liver Disease.

Tryptophan hydroxylase 1 (TPH1) has been recently suggested as a promising therapeutic target for treating obesity and fatty liver disease. A new series of 1,2,4-oxadiazolylphenyl alanine derivatives were identified as TPH1 inhibitors. Among them, compound 23a was the most active in vitro, with an IC50 (half-maximal inhibitory concentration) value of 42 nM, showed good liver microsomal stability, and showed no significant inhibition of CYP and hERG. Compound 23a inhibited TPH1 in the peripheral tissue with limited BBB penetration. In high-fat diet-fed mice, 23a reduced body weight gain, body fat, and hepatic lipid accumulation. Also, 23a improved glucose intolerance and energy expenditure. Taken together, compound 23a shows promise as a therapeutic agent for the treatment of obesity and fatty liver diseases.

Calix[4]arene-Based Triple-Stranded Metallohelicate in Water.

The title complex is a triple-stranded metallohelicate organized by the self-assembly of 5,17-difunctionalized calix[4]arenes and metal cations with octahedral coordination geometry. Due to hydrophilic triethylene glycol chains on the lower rim of the calix[4]arene, the metallohelicate can encapsulate cationic guests in water. NMR and UV-vis titration experiments reveal that the metallohelicate captures a pyridinium guest with an alanine derivative to form a host-guest complex with a host-guest ratio of 1 : 1. CD spectroscopy confirms the bias of the P- and M-helical sense of the metallohelicate by the captured guest. The metallohelicate captures two molecules of dicationic N,N'-dimethyl-DABCO and monocationic N-methyl quinuclidine, exhibiting a positive allosteric effect. 1 H NMR titration experiments indicate that the bound guests are in close proximately to the aromatic rings of the ligands. Molecular mechanics calculations based on the UV-vis and NMR observations suggest that the first guest preorganizes the conformation of the metallohelicate to facilitate access of the second guest to the cavity.

Which Stereoinductor Is Better for Asymmetric Functionalization of α-Amino Acids in a Nickel(II) Coordination Environment? Experimental and DFT Considerations.

The results of extended comparative investigation of nickel(II) Schiff base complexes (containing various auxiliary chiral moieties) commonly used as a methodological platform for the asymmetric synthesis of tailor-made α-amino acids are provided. The following issues are addressed: 1) redox activity (determining the possibility for electrochemically induced reactions); 2) quantitative estimation of the reactivity of deprotonated complexes towards electrophiles; and 3) quantum-chemical estimation of noncovalent interactions in the metal coordination environment (which shed light on the origin of the stereochemical outcome observed for different stereoinductors). Possible mechanisms that determine the relationship between the stereochemical configuration of a molecule and its electronic structure are discussed. The DFT-calculated HOMO-LUMO energies and localization, as well as relative energies for the (S)- and (R)-alanine derivatives, that determine the stereoinduction efficiency in thermodynamically controlled reactions in nickel(II) coordination are provided. The computational data are supported by experimental results on the monobenzylation of glycine derivatives.

Construction of Helically Stacked π‐Electron Systems in Poly(quinolylene‐2,3‐methylene) Stabilized by Intramolecular Hydrogen Bonds

Abstractπ‐Stacked polymers, which consist of layered π‐electron systems in a polymer, can be expected to be used in molecular electronic devices. However, the construction of a stable π‐stacked structure in a polymer is considerably challenging because it requires sophisticated designs and precise synthetic methods. Herein, we present a novel π‐stacked architecture based on poly(quinolylene‐2,3‐methylene) bearing alanine derivatives as the side chain, obtained through the living cyclo‐copolymerization of an o‐allenylaryl isocyanide. In the resulting polymer, the neighboring quinoline rings of the main chain form a layered structure with π–π interactions, which is stabilized by intramolecular hydrogen bonds. The vicinal quinoline units form two independent helices and the whole molecule is a twisted‐tape structure. This structure is established on the basis of UV/CD spectra, theoretical calculations, and atomic‐force microscopy.

Construction of Helically Stacked π-Electron Systems in Poly(quinolylene-2,3-methylene) Stabilized by Intramolecular Hydrogen Bonds.

π-Stacked polymers, which consist of layered π-electron systems in a polymer, can be expected to be used in molecular electronic devices. However, the construction of a stable π-stacked structure in a polymer is considerably challenging because it requires sophisticated designs and precise synthetic methods. Herein, we present a novel π-stacked architecture based on poly(quinolylene-2,3-methylene) bearing alanine derivatives as the side chain, obtained through the living cyclo-copolymerization of an o-allenylaryl isocyanide. In the resulting polymer, the neighboring quinoline rings of the main chain form a layered structure with π-π interactions, which is stabilized by intramolecular hydrogen bonds. The vicinal quinoline units form two independent helices and the whole molecule is a twisted-tape structure. This structure is established on the basis of UV/CD spectra, theoretical calculations, and atomic-force microscopy.

Synthesis of Nβ-Substituted α,β-Diamino Acids via Stereoselective N-Michael Additions to a Chiral Bicyclic Dehydroalanine.

The highly diastereoselective 1,4-conjugate additions of several nitrogen nucleophiles to chiral bicyclic dehydroalanines have been assessed effectively at room temperature in good to excellent yields without needing any catalyst or additional base. This methodology is general, simple, oxygen and moisture tolerant, high-yielding, totally chemo- and stereoselective. This procedure offers an efficient and practical approach for the synthesis of Nβ-substituted α,β-diamino acids, such as 1-isohistidine, τ-histidinoalanine, β-benzylaminoalanine, β-(piperidin-1-yl)alanine, β-(azepan-1-yl)alanine, and fluorescent and ciprofloxacin-containing amino acid derivatives.

Synthesis of ACE Inhibitors in Flow

Key words alanine derivatives - peptides - ACE inhibitors - coupling reagents

Adding extra-dimensions to hazelnuts primary metabolome fingerprinting by comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry featuring tandem ionization: Insights on the aroma potential

The information potential of comprehensive two-dimensional gas chromatography combined with time of flight mass spectrometry (GC × GC-TOFMS) featuring tandem hard (70 eV) and soft (12 eV) electron ionization is here applied to accurately delineate high-quality hazelnuts (Corylus avellana L.) primary metabolome fingerprints. The information provided by tandem signals for untargeted and targeted 2D-peaks is examined and exploited with pattern recognition based on template matching algorithms. EI-MS fragmentation pattern similarity, base-peak m/z values at the two examined energies (i.e., 12 and 70 eV) and response relative sensitivity are adopted to evaluate the complementary nature of signals.As challenging bench test, the hazelnut primary metabolome has a large chemical dimensionality that includes various chemical classes such as mono- and disaccharides, amino acids, low-molecular weight acids, and amines, further complicated by oximation/silylation to obtain volatile derivatives.Tandem ionization provides notable benefits including larger relative ratio of structural informing ions due to limited fragmentation at low energies (12 eV), meaningful spectral dissimilarity between 12 and 70 eV (direct match factor values range 222-783) and, for several analytes, enhanced relative sensitivity at lower energies. The complementary information provided by tandem ionization is exploited by untargeted/targeted (UT) fingerprinting on samples from different cultivars and geographical origins. The responses of 138 UT-peak-regions are explored to delineate informative patterns by univariate and multivariate statistics, providing insights on correlations between known precursors and (key)-aroma compounds and potent odorants. Strong positive correlations between non-volatile precursors and odorants are highlighted with some interesting linear trends for: 3-methylbutanal with isoleucine (R2 0.9284); 2,3-butanedione/2,3-pentanedione with monosaccharides (fructose/glucose derivatives) (R2 0.8543 and 0.8860); 2,5-dimethylpyrazine with alanine (R2 0.8822); and pyrroles (1H-pyrrole, 3-methyl-1H-pyrrole, and 1H-pyrrole-2-carboxaldehyde) with ornithine and alanine derivatives (R2 0.8604). The analytical work-flow provides a solid foundation for a new strategy for hazelnuts quality assessment because aroma potential could be derived from precursors’ chemical fingerprints.

Total Synthesis of Endolides A and B.

The total synthesis of endolides A and B has been achieved in a concise, highly stereoselective fashion (12 steps, 16.2% and 16.0% overall yields, respectively). Key features of the route include a modified Negishi coupling between 3-bromofuran and an organozinc reagent derived from an iodoalanine derivative for the synthesis of 3-(3-furyl)-alanine derivative, and a judicious choice of reaction conditions to surmount the conformational constraints placed by converting a linear peptide into the corresponding macrocycle.

Continuous Flow Synthesis of ACE Inhibitors From N-Substituted l-Alanine Derivatives.

A strategy for the continuous flow synthesis of angiotensin converting enzyme (ACE) inhibitors is described. An optimization effort guided by in situ IR analysis resulted in a general amide coupling approach facilitated by N-carboxyanhydride (NCA) activation that was further characterized by reaction kinetics analysis in batch. The three-step continuous process was demonstrated by synthesizing 8 different ACE inhibitors in up to 88 % yield with throughputs in the range of ≈0.5 g h-1 , all while avoiding both isolation of reactive intermediates and process intensive reaction conditions. The process was further developed by preparing enalapril, a World Health Organization (WHO) essential medicine, in an industrially relevant flow platform that scaled throughput to ≈1 g h-1 .

Unusual Regularity in GC Retention of Simple Amino Acid Derivatives.

Application of simple regularities and general principles along with direct use of reference gas chromatography retention index data for reliable structure determination of compounds can be enhanced by determination of new regularities that are specific to certain structural elements. Revelation and interpretation of an anomaly in the elution order of alkyl esters of alkoxycarbonyl derivatives of glycine and alanine on standard and semi-standard non-polar phases. Preliminary derivatization of amino acids to alkyl esters of N-alkoxycarbonyl analogs and interpretation of their gas chromatographic characteristics. Alkyl esters of N-alkoxycarbonyl derivatives of alanine (Alkyl = C2H5, n- and iso-C3H7) elute prior to the same derivatives of glycine, despite the presence of an additional methyl group at C(2) in the molecule. Elution order is reversed for methyl esters of N-methoxycarbonyl derivatives. It is established that the peculiar behavior of alkyl esters of N-alkoxycarbonyl derivatives of glycine and alanine agrees with the concepts of gas chromatography and the known retention index regularities of organic compounds. A decrease of retention index values is a result of an introduction of an additional methyl group to a carbon atom connected to two polar fragments in a molecule like CH2XY. The dependence of the difference of retention index values for homologs of the types of CH3-CHXY and CH2XY vs. the total mass of fragments (X + Y) is similar to those for other sub-groups of analytes.