Β-alanine Derivatives Research Articles

Surface Modification of Silica with β-Alanine Derivatives for Unique Applications in Liquid Chromatography.

Column purchasing cost is an important issue for an analyst to analyze complex sample matrices. Here, we report the development of an amino acid (β-alanine)-derived stationary phase (Sil-Ala-C12) with strategic and effective interaction sites (amide and urea as embedded polar groups with C12 alkyl chain) able to separate various kinds of analytes. Owing to the balanced hydrophobicity and hydrophilicity of the phase, it showed exceptional separation abilities in both reversed-phase high-performance liquid chromatography (RP-HPLC) as a hydrophobic phase and hydrophilic interaction chromatography (HILIC) as a hydrophilic phase. Remarkably, the baseline separation was achieved for the challenging β- and γ-isomers of tocopherol. Usually, three columns such as pentafluorophenyl or C30, C18, and sulfobetaine HILIC are required for the analysis of vitamin E, capsaicinoids, and vitamin C in chili peppers (Capsicum spp.), respectively. However, only Sil-Ala-C12 was able to separate these analytes. A single column can serve 3-4 purposes, which suggests that Sil-Ala-C12 had the potential to reduce column purchasing costs.

Discovery of potent and orally bioavailable indazole-based glucagon receptor antagonists for the treatment of type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma glucose levels. The inhibition of glucagon-induced hepatic glucose output via antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. The present work discloses the discovery of indazole-based β-alanine derivatives as potent GCGR antagonists through an efficient enantioselective synthesis and structure-activity relationship (SAR) exploration and optimization. Compounds within this class exhibited excellent pharmacokinetic properties in multiple preclinical species. In an acute dog glucagon challenge test, compound 13K significantly inhibited glucagon-mediated blood glucose increase when dosed orally at 10 mg/kg.

Molecular aggregations of bicyclodioxazastannone produced from multicomponent reactions involving functionalized 2-hydroxybenzaldehydes, α- or β-amino acids and a dimethyltin precursor

A series of novel bicyclodioxazastannone derived from ONO Schiff base ligands prepared from diazenylaryl functionalized 2-hydroxybenzaldehydes and α or β-amino acetates, viz., [Me2Sn(L1)]2 (1), [Me2Sn(L2)]2 (2), [Me2Sn(L3)(MeOH)]2 (3), [Me2Sn(L4)]n (4), [Me2Sn(L5)]n⋅nH2O (5), [Me2SnL6)]2 (6), [Me2Sn(L7)] (7A), [Me2Sn(L7)]2⋅C8H10 (7B) and [Me2Sn(L8)]n (8), with variously substituted Schiff bases L1-L8 generated in situ, were synthesized and structurally characterized. The crystal structures of compounds 1–8 revealed different structure types with five-, six- or seven-fold coordination of the metal center. Except for 7A, which crystallized in the form of a discrete mononuclear tin complex, intermolecular association through O→Sn interactions was observed. The resulting aggregates were molecular dimers with a central four-membered Sn2O2 ring (1, 2, 6 and 7A), 1D coordination polymers (4, 5 and 8) and a solvent adduct linked through both O–H⋅⋅⋅O hydrogen bonds and O⋅⋅⋅Sn contacts (3). In the presence of hydrogen bond donors such as O–H and N–H groups in the ligands, the molecular structures are further interconnected through O/N–H⋅⋅⋅O hydrogen bonds, giving in combination with the O⋅⋅⋅Sn contacts overall 2D layer-type assemblies. In solution, contrary to the β-alanine derivative 1, the 1H and 13C NMR spectra of compounds 2–8 displayed signals for the Me2Sn moieties because of diastereotopic environments according to the asymmetric nature of the ligand. The 119Sn NMR data of most of the compounds were acquired in DMSO‑d6 with the chemical shift displacements indicating six-coordinate tin atoms, which is in good agreement with the O→Sn adduct formation in the solid-state structures. The 119Sn NMR spectrum of compound 2 measured in CDCl3 indicates the presence of a mononuclear tin complex, as expected for a non-coordinating solvent.

ОКРЕМІ ВИПАДКИ УТВОРЕННЯ о-АЛКОКСИКОРИЧНИХ КИСЛОТ НА ОСНОВІ КУМАРИНІВ В УМОВАХ O-АЛКІЛЮВАННЯ

A number of new derivatives of o-alkoxy cinnamic acids were obtained from various coumarins by opening the lactone fragment and O-alkylation of the endocyclic Oxygen atom. The α-hetaryl-β-(2-alkoxy-5-chlorophenyl)cinnamic acids were obtained from 3-(benzothiazol-2-yl)-6-chlorocoumarin and 3-(benzimidazol-2-yl)-6-chlorocoumarin by treatment with diluted alkali followed by p-methylbenzyl chloride or dimethyl sulfate addition, respectively. A similar reaction stages (opening in aqueous alkali and alkylation of the phenolate anion) was applied to the synthetic analogues of psoralen – 5-methylfuro[3,2-g]coumarins with various substituents in the furan fragment. Thus it was possible to obtain a number of 3- and 4-substituted 3-(6-alkoxybenzofuran-5-yl)but-2-enoic acids. But in this case, the conversion of the starting furo[3,2-g]coumarins to cinnamic acid derivatives was not complete even after long time of reaction with a big excess of an alkylation agent. Therefore, the necessary step is the separation of the target acid from unreacted coumarin by dissolving the product in a saturated NaHCO3 solution. The insoluble part is a practically pure starting material, which can be recycled in the reaction; so the total yield of the product would be increased. To demonstrate the synthetic abilities of 3-(6-alkoxybenzofuran-5-yl)but-2-enoic acids these compounds were used in synthesis of amides with pharmacophore fragments: a phenethylamine derivative with an additional sulfamide group and a β-alanine derivative. The experiments showed that the 3-azolylcoumarins and furo[3,2-g]coumarins coumarin cycle's opening occurs only in aqueous alkali, and when alkylated in an organic solvent in the presence of K2CO3, the lactone fragment remains unchanged. The 7-hydroxy-6-(isocoumarin-3-yl)-4-methylcoumarin cycle turned out to be more labile. The result of alkylation of this compound with ethyl acetate of chloroacetic acid in the presence of K2CO3 depended on the nature of the aprotic solvent and the temperature of reaction. So, when this reaction was carried out in boiling acetone, only the free hydroxyl group at position 7 of coumarin was alkylated. But when the initial coumarin was heated at 100°С with an excess of an alkylating agent in DMSO, simultaneous alkylation of both the free 7-OH group and the endocyclic Oxygen atom occurred.

Amino acid modified [70] fullerene derivatives with high radical scavenging activity as promising bodyguards for chemotherapy protection

Despite the great efforts for tumor therapy in the last decades, currently chemotherapy induced toxicity remains a formidable problem for cancer patients, and it usually prohibits the cancer therapy from successful completion due to severe side effects. In general, the main side effects of chemotherapeutic agents are from the as-produced reactive oxygen species (ROS) that not only harm the tumor cells but also damage the patients’ organs. Here we report the application of amino acid derivatives of fullerene (AADF) in the chemotherapy which strongly scavenge the excess ROS to protect the tested mice against the chemotherapy-induced hepatotoxicity and cardiotoxicity. Two amino acids, i.e., L-lysine and β-alanine were separately employed to chemically modify C70 fullerene, and L-lysine derivative of fullerene (C70-Lys) exhibits superior radical scavenging activity to β-alanine derivative of C70 (C70-Ala). As expected, C70-Lys show much better protective effect than C70-Ala against the chemotherapy injuries in vivo, which is verified by various histopathological, haematological examinations and antioxidative enzyme studies. Moreover, the L-glutathione level is increased and the cytochrome P-450 2E1 expression is inhibited. They are potentially developed as promising bodyguards for chemotherapy protection.

Exploring Orthogonal Hydrogen Bonding towards Designing Organic-Salt-Based Supramolecular Gelators: Synthesis, Structures, and Anticancer Properties.

A series of primary ammonium monocarboxylate (PAM) salts derived from β-alanine derivatives of pyrene and naphthalene acetic acid, along with the parent acids, were explored to probe the plausible role of orthogonal hydrogen bonding resulting from amide⋅⋅⋅amide and PAM synthons on gelation. Single-crystal X-ray diffraction (SXRD) studies were performed on two parent acids and five PAM salts in the series. The data revealed that orthogonal hydrogen bonding played an important role in gelation. Structure-property correlation based on SXRD and powder X-ray diffraction data also supported the working hypothesis upon which these gelators were designed. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and cell migration assay on a highly aggressive human breast cancer cell line, MDA-MB-231, revealed that one of the PAM salts in the series, namely, PAA.B2, displayed anticancer properties, and internalization of the gelator salt in the same cell line was confirmed by cell imaging.

Carbon nanotubes functionalized with folic acid attached via biomimetic peptide linker.

Anchoring folic acid (FA) with a biomimetic peptidic linker resistant to proteolytic degradation to act as a homing device on functionalized carbon nanotubes. Ethylenediamine was attached to oxidized multiwalled carbon nanotubes (MWNTs) using 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methylmorpholinium tetrafluoroborate.FA was coupled with 6-aminohexanoic acid and derivatives of β-alanine, affording four intermediates, which connected to the MWNTs via peptidic linkers of various lengths. Biomimetic nanomaterials were produced with FA as a homing molecule. The structure and properties of the nanomaterials were analyzed, confirming the versatility of the peptides used as linkers. Conjugates of FA attached to MWNTs via peptide linkers prepared from β-alanine residues are resistant to proteolytic degradation. Viability in colon cancer cells and normal colonocytes confirmed their lack of cytotoxicity.

Rationally Developed Organic Salts of Tolfenamic Acid and Its β-Alanine Derivatives for Dual Purposes as an Anti-Inflammatory Topical Gel and Anticancer Agent.

A new series of primary ammonium monocarboxylate (PAM) salts of a nonsteroidal anti-inflammatory drug (NSAID), namely, tolfenamic acid (TA), and its β-alanine derivatives were generated. Nearly 67 % of the salts in the series showed gelling abilities with various solvents, including water (biogenic solvent) and methyl salicylate (typically used for topical gel formulations). Gels were characterized by rheology, electron microscopy, and so forth. Structure-property correlations based on single-crystal and powder XRD data of several gelator and nongelator salts revealed intriguing insights. Studies (in vitro) on an aggressive human breast cancer cell line (MDA-MB-231) with the l-tyrosine methyl ester salt of TA (S7) revealed that the hydrogelator salt was more effective at killing cancer cells than the mother drug TA (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay); displayed better anti-inflammatory activity compared with that of TA (prostaglandin E2 assay); could be internalized within the cancer cells, as revealed by fluorescence microscopy; and inhibited effectively migration of the cancer cells. Thus, the easily accessible ambidextrous gelator salt S7 can be used for two purposes: as an anti-inflammatory topical gel and as an anticancer agent.

Probing the formation of supramolecular assemblies of amphiphilic N-methyl glycine and N,N dimethyl β-alanine derivatives

Supramolecular assemblies were prepared using new amphiphilic dervivatives ofN-methyl gylcine andN,Ndimethyl-β-alanine.

Synthesis and Evaluation of Novel 7- and 8-Aminophenoxazinones for the Detection of β-Alanine Aminopeptidase Activity and the Reliable Identification of Pseudomonas aeruginosa in Clinical Samples.

A series of novel 8-aminophenoxazin-3-one and 7-aminophenoxazin-3-one chromogens and their corresponding β-alanine derivatives were synthesized and evaluated for their ability to detect β-alanyl aminopeptidase activity in bacteria known to hydrolyze β-alanine derivatized substrates. The results provided insight into the structural requirements for effective visualization of enzymatic activity and the mechanism of formation of phenoxazinon-3-ones. 8-Aminophenoxazin-3-one substrates 23c, 23d, and 23e were prepared in good to high overall yield and were selective for β-alanyl aminopeptidase activity in bacteria, producing a lighter agar background coloration facilitating visualization of colored colonies, with variable localization to the colonies, but had lower sensitivities for the detection of Pseudomonas aeruginosa in comparison to the analogous 7-aminophenoxazin-3-one substrates. The synthetic methodology employed here allows the preparation of a range of substrates for evaluation and the establishment of structure-activity relationships. For example, the 2-pentyl substituted aminophenoxazin-3-one 22b performed with analogous sensitivity to the corresponding 1-pentyl-7-aminophenoxazin-3-one substrate 1 used commercially, highlighting that the position of the pentyl substituent can be varied while maintaining detection sensitivity.

Copolymers containing functional groups intrinsic to the active centers of serine hydrolases: Synthesis and evaluation of catalytic capability

N-Acryloyl derivatives of histamine, monoethanolamine, and β-alanine, which contain imidazole, hydroxyl, and carboxyl functional groups, respectively, are synthesized and characterized. Copolymers, which are further divided into thermally precipitable and thermally nonprecipitable (soluble) fractions, are obtained via the free-radical copolymerization of N-vinylcaprolactam and the specified comonomers that is initiated by a persulfate–tertiary amine redox system in a medium of 10% aqueous dimethyl sulfoxide (DMSO) at 65°C. It is shown that the soluble fractions of the synthesized copolymers exhibit catalytic activity in the reaction of hydrolysis of 4-nitrophenyl propionate (NPP) at a temperature above the coil-to-globule transition.

The second example for a cubane-like copper(II) complex in a series of N-hydroxyalkyl β-alanine derivatives

A new tetranuclear cubane-like copper(II) complex [Cu4(HL1)4] based on N-(1,1-dihydroxymethyl)ethyl-βalanine (H3L1) is synthesized. Its structure is studied by X-ray diffraction analysis (CIF file CCDC 1020735). In the crystal structure of the complex, the copper atoms are joined into tetrahedra with the distances Cu⋯Cu 3.139–3.456 A supplemented to cubanes by the μ3-bridging oxygen atoms of the hydroxymethyl groups. The coordination environment of each metal center is a distorted octahedron. The (HL1)2− ligand is doubly protonated and performs the hexadentate chelate-(μ3-bridging) function to form the alkoxocarboxylate chelate of copper(II).

Synthesis and chemoinformatics analysis of N-aryl-β-alanine derivatives

Carbohydrazides of N-substituted β-amino acids exhibit a variety of different biological activities including antibacterial, antiviral, fungicidal, antihelminthic, anticancer, antiinflammatory, etc. New potentially biologically active N-(4-iodophenyl)-β-alanine derivatives, N-(4-iodophenyl)-N-carboxyethyl-β-alanine derivatives, and their cyclization products were designed and synthesized. To determine the most propitious directions for further investigation of the obtained compounds, we tried to appraise their biological activity in silico using the ChemSpider and chemical structure lookup service (CSLS), chemical similarity assessment (Integrity and SuperPred), and machine learning methods [prediction of activity spectra for substances (PASS)]. No useful hints on potential biological activity of the obtained novel compounds were delivered by ChemSpider, CSLS, Integrity or SuperPred. In contrast, PASS predicted some biological activities that could be verified experimentally. Neither antibacterial nor antifungal activity was predicted for the compounds under study despite these actions being known for compounds from this chemical class. Evaluation of antibacterial (Escherichia coli B-906, Staphylococcus aureus 209-P, and Mycobacterium luteum B-91) and antifungal (Candida tenuis VKM Y-70 and Aspergillus niger F-1119) activities in vitro did not reveal any significant antimicrobial action, which corresponds to the computational prediction. Advantages and shortcomings of chemical similarity and machine learning techniques in computational assessment of biological activities are discussed. Based on the obtained results, we conclude that academic organic chemistry studies could provide a significant impact on drug discovery due to the novelty and diversity of the designed and synthesized compounds; however, practical utilization of this potential is narrowed by the limited facilities for assaying biological activities.

Synthesis and antimicrobial activity of N-(4-chlorophenyl)-β-alanine derivatives with an azole moiety

N-(4-Chlorophenyl)-β-alanine was shown to be a useful synthetic intermediate for synthesis of azole heterocycles. Their structure was characterized by IR, mass, and NMR spectroscopy, and elemental analysis. Some of the synthesized compounds had antibacterial activity against Rhizobium radiobacter, as determined by use of the diffusion technique.

Synthesis of 5-amino-2-aminoalkyl-1,3-oxazol-4-ylphosphonic acid derivatives and their use in the preparation of phosphorylated peptidomimetics

Starting from phthalimidoalkanoylamines 1 (amino-protected derivatives of glycine, β-alanine, γ-amino butyric, δ-amino valeric, and ε-amino caproic acids), a facile synthetic method has been developed to obtain diethyl 5-alkyl(dialkyl)amino-2-aminoalkyl-1,3-oxazol-4-ylphosphonates 7, which have been further used in the preparation of phosphorylated peptidomimetics 10 and 12.

Synthesis of (S)-2-[(dioctylphosphoryl)methylamino]propionic acid from trimethylsilyl 2-(trimethylsilylamino)propanoate

We previously showed [1] that the Kabachnik– Fields reaction in the system dioctylphosphine oxide– paraformaldehyde–amino acid leads to the formation of the corresponding N-(dioctylphosphorylmethyl)substituted amino acid derivatives. In particular, N-phosphorylmethyl derivatives of glycine, β-alanine, and N-butylglycine were synthesized in this way. Because of poor solubility of amino acids in organic solvents, the reactions were carried out in acetonitrile in the presence of the corresponding amino acid hydrochloride. We made an attempt to perform phosphorylation of (S)-α-alanine under similar conditions. However, the reaction in heterogeneous medium gave a mixture of monoand bisphosphorylation products. With a view to improve the selectivity, the Kabachnik– Fields reaction was carried out with dioctylphosphine oxide, paraformaldehyde, and trimethylsilyl (S)-2-(trimethylsilylamino)propanoate prepared by heating of (S)-α-alanine with excess hexamethyldisilazane over a period of 72 h under reflux. Heating of the reactants in boiling toluene in the presence of p-toluenesulfonic acid (reaction time 3 h) afforded 96% (according to the P–{H} NMR data) of silylated aminomethylphosphine oxide I. Silylamine I was treated with a hot 15% aqueous solution of sodium hydroxide, and the subsequent neutralization of sodium salt II with 10% aqueous HCl gave target acid III. (S)-2-{[(Dioctylphosphoryl)methyl](trimethylsilyl)amino}propionic acid (I). White amorphous substance. H NMR spectrum (CDCl3), δ, ppm: 0.21 s [9H, Si(CH3)3], 0.86 d (3H, CH3, JHH = 9 Hz), 1.25– 1.90 m (34H, C8H17), 2.88 d.d (2H, CH2P, JHH = 4, JPH = 18 Hz), 3.27 q (1H, CH, JHH = 9 Hz). P–{H} NMR spectrum (PhMe): δP 51.2 ppm, s. (S)-2-[(Dioctylphosphoryl)methylamino]propionic acid (III). White crystalline substance, mp 132°C. H NMR spectrum (CDCl3), δ, ppm: 0.87 d (3H, CH3, JHH = 9 Hz), 1.25–1.90 m (34H, C8H17), 2.89 d.d (2H, CH2P, JHH = 4, JPH = 18 Hz), 3.27 q (1H, CH, JHH = 9 Hz). P–{H} NMR spectrum (CH2Cl2): δP 52.4 ppm, s. The H and P–{H} NMR spectra were recorded on a Varian XL-300 spectrometer a t 300 and 122.4 MHz, respectively. This study was performed under financial support by the Russian Foundation for Basic Research (project no. 13-03-00 536).

In Vivo Cleavage Rate of a Dextran-bound Magnetic Resonance Imaging Contrast agent: Preparation and Intravascular Pharmacokinetic Characteristics in the Rabbit

Earlier described dextran-based contrast agents for magnetic resonance imaging (MRI) comprising the gadolinium chelate diethylenetriamine pentaacetic acid (GdDTPA, 1) have shown significantly shorter in vivo contrast duration in rat than what would be expected from the initial average molecular weight (Mw) of the dextran fraction (71.4 kD). To investigate this further, four dextran fractions with given initial average molecular weight (Mw) of 10.4, 41.0, 71.4 and 580 kD were used as starting material to prepare products 2-5 where one of the carboxylic acid functionalities in GdDTPA was used as a direct covalent ester linker to hydroxyl groups in dextrans. A fifth derivative (6) was an amide-ester bound β-alanine-DTPAGd conjugate with dextran having Mw 71.4 kD. The reference compound GdDTPA (1) and gadoliniumlabelled dextran derivatives 2-6 were injected intravenously in rabbits. Pharmacokinetic parameters showed that when GdDTPA is ester-bound directly to dextran hydroxyls, the cleavage rates of 2-5 were only moderately dependent on the molecular weights of the dextrans, having blood pool half-lives comparable to the low-molecular reference compound (t 1/2,β 0.3 - 0.5 hrs.). Presence of a β-alanine spacer in 6 prolonged the plasma half-life t 1/2,β to 6.9 hours, rendering a blood residence time suitable for blood pool slow release of GdDTPA. Biological cleavage regenerates the clinically acceptable carrier dextran and the β-alanine derivative of GdDTPA, pointing at a clinically acceptable product class for blood-pool contrast in MRI.

New biocatalytic route for the production of enantioenriched β-alanine derivatives starting from 5- and 6-monosubstituted dihydrouracils

Taking advantage of the catalytic promiscuity of pyrimidine-catabolism enzymes (dihydropyrimidinase (E.C. 3.5.2.2), N-carbamoyl-β-alanine amidohydrolase (E.C. 3.5.1.6)), the production of different β-alanine derivatives starting from 5- and 6-monosubstituted dihydrouracils has been evaluated using a mimesis approach. In this work, the S-enantioselective character of dihydropyrimidinase from Sinorizhobium meliloti toward 6-monosubstituted dihydrouracil derivatives has been shown. An inverted R-/S-enantioselectivity of N-carbamoyl-β-alanine amidohydrolase from Agrobacterium tumefaciens toward two different N-carbamoyl-β-amino acids has been proved. Our results have shown for the first time that this mimetic tandem constitutes an interesting biotechnological tool for the preparation of different β-alanine derivatives in an environmentally friendly way, allowing the production of enantioenriched (R)-α-phenyl-β-alanine (e.e.>95%) and (R)-α-methyl-β-alanine (e.e.>90%).

Crystal and molecular structure of N-(4-nitrophenyl)-β-alanine—Its vibrational spectra and theoretical calculations

The N-(4-nitrophenyl)-β-alanine in crystalline form directly by the addition of 4-nitroaniline to the acrylic acid in aqueous solution has been obtained. The title β-alanine derivative crystallizes in the P2 1/ c space group of monoclinic system with four molecules per unit cell. The X-ray geometry of β-alanine derivative molecule has been compared with those obtained by molecular orbital calculations corresponding to the gas phase. In the crystal the molecules related by an inversion center interact via symmetrically equivalent O–H⋯O hydrogen bonds with O⋯O distance of 2.656(2) Å forming a dimeric structure. The dimers of β-alanine derivative weakly interact via N–H⋯O hydrogen bonds between the H atom of β-amine groups and one of O atom of nitro groups. The room temperature powder vibrational (infrared and Raman) measurements are in accordance with the X-ray analysis. In aqueous solution of 4-nitroaniline and acrylic acid, the double C C bond of vinyl group of acrylic acid breaks as result of 4-nitroaniline addition.

Synthesis of N-(2-hydroxyethyl) derivatives of β-alanine

Synthesis of N-(2-hydroxyethyl) derivatives of β-alanine