Amino Acid Esters Research Articles

Neurotherapeutic Potential of Water-Soluble pH-Responsive Prodrugs of EIDD-036 in Traumatic Brain Injury.

The C-20 oxime of progesterone, EIDD-036 (2), demonstrates neuroprotection and improved outcomes in animal models of traumatic brain injury (TBI). However, 2 suffers from poor solubility, which renders it unsuitable for rapid administration. Previous prodrugs of 2 aimed at improving solubility by incorporating enzymatically labile amino acid and phosphate ester promoieties. These approaches were effective but led to limitations with in vivo administration. Herein, we disclose a pH-responsive water-soluble prodrug strategy to improve exposure to 2 through enzyme-independent activation. Compound 13l was identified as a lead that exhibits water-solubility, stability in acidic solutions, and rapid conversion to 2 at physiological pH. Administration of 13l to rats resulted in a twofold increase in exposure to 2 compared to the previous generation phosphate prodrug, EIDD-1723 (6). In a rat model of TBI, treatment with 13l resulted in a significant decrease in cerebral edema when administered postinjury.

EVALUATION AND COMPARISON OF THE ANTIMICROBIAL AND CYTOTOXIC ACTIVITIES OF SOME AMINO ACID METHYL ESTERS

In this study, the antibacterial and cytotoxic activities of some amino acid methyl esters (L-methionine, L-phenylalanine, L-histidine, L-lysine, L-tryptophan, and L-tyrosine) were investigated. The effect of amino acid methyl ester compounds on antibacterial performance was determinated against Gram-negative and Gram-positive bacteria. The effect of amino acid esters on cell viability was investigated against cancerous and non-cancerous cell lines using the MTS assay. The results showed the substances had low antimicrobial effect on both Gram-negative and Gram-positive bacteria. In addition, it was found that the studied substances did not have a toxic effect on cell growth in non-cancerous cells. For this reason, it is thought that the results obtained will contribute to research on new synthesizable compounds based on amino acid esters and studies on drug development.

Arylation of Cyclopropanol with Pyrrole: Asymmetric Synthesis of Indolizidine 167B, Indolizidine 209D, and Monomorine I

A Fe(NO3)3-mediated ring-opening arylation of cyclopropanol with the electron-rich pyrrole has been developed, which might proceed through oxidative radical ring opening of cyclopropanol followed by cyclization to the pyrrole motif and then aromatization. This method enables direct arylation of cyclopropanol without prefunctionalization and thus allows rapid access to a diverse array of chiral 5,6,7,8-tetrahydroindolizines from easily available chiral amino acid esters. The synthetic utility has been demonstrated by the asymmetric synthesis of alklaoids (-)-indolizidine 167B, (+)-indolizidine 209D, (+)-monomorine I, and a natural product analogue.

Asymmetric rotations and dimerization driven by normal to modulated phase transition in 4-biphenylcarboxy coupled L-phenylalaninate.

Amongst the derivatives of 4-biphenylcarboxylic acid and amino acid esters, the crystal structure of 4-biphenylcarboxy-(L)-phenylalaninate is unusual owing to its monoclinic symmetry within a pseudo-orthorhombic crystal system. The distortion is described by a disparate rotational property around the chiral centers (ϕchiral ≃ -129° and 58°) of the two molecules in the asymmetric unit. Each of these molecules comprises planar biphenyl moieties (ϕbiphenyl = 0°). Using temperature-dependent single-crystal X-ray diffraction experiments we show that the compound undergoes a phase transition below T ∼ 124 K that is characterized by a commensurate modulation wavevector, q = δ(101), δ = ½. The (3+1)-dimensional modulated structure at T = 100 K suggests that the phase transition drives the biphenyl moieties towards noncoplanar conformations with significant variation of internal torsion angle (ϕmaxbiphenyl ≤ 20°). These intramolecular rotations lead to dimerization of the molecular stacks that are described predominantly by distortions in intermolecular tilts (θmax ≤ 20°) and small variations in intermolecular distances (Δdmax ≃ 0.05 Å) between biphenyl molecules. Atypical of modulated structures and superstructures of biphenyl and other polyphenyls, the rotations of individual molecules are asymmetric (Δϕbiphenyl ≈ 5°) while ϕbiphenyl of one independent molecule is two to four times larger than the other. Crystal-chemical analysis and phase relations in superspace suggest multiple competing factors involving intramolecular steric factors, intermolecular H-C...C-H contacts and weak C-H...O hydrogen bonds that govern the distinctively unequal torsional properties of the molecules.

Rhein–Amino Acid Ester Conjugates as Potential Antifungal Agents: Synthesis and Biological Evaluation

In the search for crop protectants, amino acid ester conjugates have been widely investigated as potential antifungal agents. In this study, a series of rhein-amino acid ester conjugates were designed and synthesized in good yields, and their structures were confirmed by 1H-NMR, 13C-NMR and HRMS. The bioassay results revealed that most of the conjugates exhibited potent inhibitory activity against R. solani and S. sclerotiorum. In particular, conjugate 3c had the highest antifungal activity against R. solani with an EC50 value of 0.125 mM. For S. sclerotiorum, conjugate 3m showed the highest antifungal activity with an EC50 value of 0.114 mM. Satisfactorily, conjugate 3c exhibited better protective effects than that of the positive control, physcion, against powdery mildew in wheat. This research supports the role of rhein-amino acid ester conjugates as potential antifungal agents for plant fungal diseases.

Theoretical Mechanistic Investigation of the Dynamic Kinetic Resolution of N-Protected Amino Acid Esters using Phase-Transfer Catalysts.

A detailed theoretical mechanistic investigation on the dynamic kinetic resolution of N-protected amino acid esters using phase-transfer catalysts is described. Semiautomatic exhaustive conformation search of transition state (TS)-like structures were carried out using the ConFinder program and the pseudo-TS conformational search (PTSCS) method. This conformational search method successfully provided reasonable TS structures for determining the stereoselectivity in the asymmetric base hydrolysis of hexafluoroisopropyl (HFIP) esters as well as the racemization mechanism. Furthermore, the independent gradient model (IGM) analysis of the TS structures suggested that the H-bonding interactions with the oxyanion hole and π-stacking interactions are the common important features of the proposed TS structures that determine the stereoselectivity.

Nickel-catalyzedN-arylation of optically pure amino acid esters with activated (hetero)aryl electrophiles

An efficient method for the C–N cross-coupling of (hetero)aryl (pseudo)halides with optically pure α-amino acid esters employing a commercially available nickel catalyst and weak inorganic base was developed. This is the first example of Ni-catalyzed N-arylation of amino acid esters without the use of electrochemistry, which was shown to effectively couple a variety of amino acid tert-butyl esters with (hetero)aryl chlorides, bromides, and tosylates in high yields and excellent enantioretention. Base-mediated racemization was revealed during control experiments, but increasing the steric bulk of the amino acid ester group limited the amount of racemization of the product.

Stereoselective synthesis of backbone extended π-conjugated amino esters.

Utilization of the Wittig reaction to synthesize conjugative multiple double bonds is rare. We examined the utility of the Wittig reaction to construct conjugative two and three carbon-carbon double bonds on the N-protected amino acid backbone. The ethyl esters of N-Boc amino acids with multiple carbon-carbon double bonds in the backbone were isolated in excellent yields with exceptional E-selectivity of the double bonds. The allylic alcohols of α,β-unsaturated γ-amino esters were selectively synthesized from the DIBAL-H and BF3·OEt2. The allylic alcohols were transformed into aldehydes using IBX oxidation. Using this protocol, we synthesized ethyl esters of N-Boc-(E,E)-α,β,γ,δ-unsaturated ε-amino acids with various side-chain functionalities and ethyl esters of N-Boc-(E,E,E)-α,β,γ,δ,ε,ζ-unsaturated η-amino acids with excellent yields. We speculated the exceptional E-selectivity is probably due to the stabilization of the planar transition state of the Wittig reaction with the double bond p-orbitals. No racemization was observed in the synthesis of amino acids. The reported process may serve as an excellent route to synthesize multiple conjugative carbon-carbon double bonds.

Trimethylaluminum-mediated one-pot peptide elongation.

Efficient and straightforward peptide bond formation of N-, and C-terminal unprotected amino acids was successfully achieved by using trimethylaluminum. The coupling reaction was accomplished by pre-reaction of N-, and C-terminal unprotected amino acids and trimethylaluminum to form a five-membered ring that smoothly reacted with nucleophilic amino acid esters. This simple and highly efficient reaction system allows one-pot tripeptide synthesis without the need for expensive coupling reagents. Furthermore, peptide bond formation can be effectively achieved even for amino acids with bulky substituents at the side chain to afford the corresponding tripeptides in high yields in a one-pot manner. In addition, the reaction can be applied for further peptide elongation by the subsequent addition of amino acids and trimethylaluminum. We anticipate that this cost-effective, straightforward, and efficient protocol will be useful for the synthesis of a wide variety of peptides.

Chiral aldehyde catalysis enables direct asymmetric α-substitution reaction of N-unprotected amino acids with halohydrocarbons.

The direct catalytic α-hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to α,α-disubstituted non-proteinogenic α-amino acid compounds. However, all the reported methodologies depend on N-protected amino acids as starting materials. Herein, we report on three highly efficient aldehyde-catalyzed direct α-hydrocarbylations of N-unprotected amino acid esters with aryl-, allyl-, and benzyl halides. By promoting a simple chiral BINOL-aldehyde catalyst or combining catalysts of a chiral aldehyde and Lewis acid ZnCl2, the asymmetric α-arylation, α-allylation, and α-benzylation of amino acid esters with the corresponding halohydrocarbons proceed smoothly, producing α,α-disubstituted α-amino acids in moderate-to-high yields and good-to-excellent enantioselectivities. The asymmetric α-arylation reaction can be applied in the formal synthesis of the clinical candidate compound (+)-AG-041R. Based on the results given by control experiments, three reaction models are proposed to illustrate the stereoselective-control outcomes.

Modular construction of N-arylated amino acid esters enabled by a photoredox-catalyzed multicomponent reaction

An efficient photoredox-catalyzed three-component coupling reaction of aryl amine, glyoxalate and alkyltrifluoroborates has been reported.

Изучение антибактериальных свойств новых производных кофеина в отношении условно-патогенных бактерий in vitro

Introduction. The resistance of microbes to many classes of antimicrobial drugs is a global threat to human health and necessitates the search for new compounds with antimicrobial activity, with low toxicity and a potentially wide range of biological activity. Aim. To study in vitro the ability of new xanthine derivatives (caffeine, 1-butyltheobromine and 7-butyltheophylline) to inhibit growth Staphylococcus (S.) aureus, Bacillus (B.) cereus, Escherichia (E.) coli and Pseudomonas (P.) aeruginosa. Materials and methods. The antibacterial activity of xanthine derivatives synthesized in the Laboratory of Medicinal Chemistry of the N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry was studied in vitro using serial dilutions in a liquid nutrient medium against S. aureus, B. cereus, E. coli and P. aeruginosa cultures. Results. Three substances, including the starting material – caffeine and 7-butyltheophylline, did not show antibacterial properties against test microbes. All xanthine derivatives studied did not inhibit the growth of E. coli and P. aeruginosa; 9 compounds containing fragments of amino acid esters or an acetylene substituent in the position of the C-8 xanthine backbone showed antibacterial activity against S. aureus and (or) B. cereus. Conclusion. When studying the ability of natural xanthine caffeine and 12 of its derivatives to inhibit the growth of cultures of opportunistic bacteria, antibacterial properties against S. aureus and B. cereus were revealed in a number of amino acid derivatives. The best effect was shown by compounds containing fragments of alpha- and beta-amino acid esters (L-valine and beta-phenyl-beta-alanine), which determines the prospects for further research.

Proteases: An overview on its recent industrial developments and current scenario in the revolution of biocatalysis

In recent years there is tremendous growth in the utilization of alkaline protease as an industrial catalyst. The extensive usage of chemicals for various applications in industries is usually associated with severe health effects and environmental problems. In this context, the scientific world mainly aims to substitute these toxic compounds with healthy environmental benign products for a good life. So, the chemicals are replaced by various enzymes among which microbial enzymes especially proteases are mostly employed in the modern corporate sectors in the manufacture of detergents, leather, food products and also in waste management techniques. The present review summarizes the various industrial applications of alkaline protease, different factors influencing its production like isolation source, optimum pH, temperature, the effect of inhibitor and metal ions on alkaline protease producing microorganisms. Furthermore the biocatalytic activity of alkaline protease in various organic transformations namely Knoevenagel condensation, Domino reaction, Aldol reaction, transesterification reaction, resolution of amino acids in organic solvents, kinetic resolution of carboxylic acids, strained amides, peptide synthesis by alcalase cross-linked enzyme aggregates (CLEA), enantioselective hydrolysis of prochiral dinitril, enzymatic desymmetrization of Ganciclovir, enantioselective aminoacid ester hydrolysis and fragmentation of p-amido benzyl ethers have been compiled in the current review.

Biphenyl aldehyde-based ternary catalytic system catalyzed Tsuji–Trost allylation of N-unprotected amino acid esters

A highly efficient biphenyl aldehyde-based ternary catalytic system is rationally designed and applied in the direct α-allylation reaction of N-unprotected amino acid esters and allyl alcohol acetates. The chemoselectivity of C-allylation and N-allylation is efficiently controlled and various racemic α,α-disubstituted amino acid esters are generated in good-to-high yields. The target products can be readily converted into structurally diverse α,α-disubstituted amino acids at a gram scale.

Derivatives of 3′‐Azidothymidine with 6‐Cyanopyridone as Base or as Phosphoramidate Ester and their Antiretroviral Activity

AbstractStrongly pairing ethynylpyridone C‐nucleosides are attractive surrogates for thymidine in oligonucleotides. Exploratory work on the antiviral activity of 3′‐azidothymidine (AZT) derivatives with ethynylpyridone as base had identified strong lipophilicity as a limiting factor. Two strategies are being pursued to overcome this issue. In order to make the base more polar, the ethynyl group has been replaced with a cyano group, leading to a cyanopyridone C‐nucleoside, whose eleven‐step synthesis is reported here, together with the synthesis of a 3′‐azido‐2′,3′‐dideoxynucleoside derivative. The base pairing with adenine in a DNA duplex was studied by UV melting analysis of a self‐complementary hexamer containing the 6‐cyano‐2′‐deoxynucleoside instead of thymidine. A melting point increase of 2 °C compared to the unmodified control was found. The other strategy employs a phosphoramidate prodrug design with less lipophilic amino acid esters. Here, anti‐HIV test of the alaninyl and prolinyl methyl esters of AZT gave promising results in cell culture experiments, increasing the selectivity index up to 5.8‐fold for the IIIB strain and up to 5‐fold for the ROD strain of the virus, as compared to the parent nucleoside. These findings help to design the next generation of pyridone C‐nucleosides with potential applications as antivirals.

Enhancing the solubility and antimicrobial activity of cellulose through esterification modification using amino acid hydrochlorides

Most amino acid molecules have good water solubility and are rich in functional groups, which makes them a promising derivatizing agent for cellulose. However, self-condensation of amino acids and low reaction efficiency always happen during esterification. Here, amino acid hydrochloride ([AA]Cl) is selected as raw material to synthesize cellulose amino acid ester (CAE). Based on TG-MS coupling technology, a significantly faster reaction rate of [AA]Cl compared to raw amino acid can be observed visually. CAE with the degree of substitution 0.412–0.516 is facilely synthesized under 130–170 °C for 10–50 min. Moreover, the effects of amounts of [AA]Cl agent, temperature, and time on the esterification are studied. The CAE can be well dissolved in 7 wt% NaOH aq., resulting in a 7.5 wt% dope. The rheological test of the dope demonstrated a shear-thinning behavior for Newtonian-like fluid, and a high gel temperature (41.7 °C). Further, the synthesized products show distinct antibacterial activity and the bacteriostatic reduction rate against E. coli can reach 99.5 %.

Completely stereospecific synthesis of a molecular cinquefoil (51) knot

<h2>Summary</h2> Although several molecular prime knots have been prepared to date, their stereoselective synthesis is still a rare occurrence. Here, we report a two-step, completely stereospecific preparation of a molecular cinquefoil (5₁) knot in 86% yield. The knotted product is generated from the covalent capture of a pentameric circular helicate. The absolute configuration of amino acid ester within the ligand strand directly determines the helical chirality of the circular helicate, the handedness, and the topological writhe of the knot. An open helicate features layered packing in the solid state, providing a scaffold for molecularly woven polymers. Several anions bind weakly to the well-organized central cavity of the knot through hydrogen bonding. Topological chirality alone induces all-important changes in the environment around the chromophores. Transfer of chirality in knot synthesis opens up opportunities for the assembly of other chiral nanotopologies and exploring the consequences of topological stereochemistry in chemistry, materials, and biology.

Solid superacid SO42−-S2O82−/SnO2-Nd2O3-catalyzed esterification of α-aromatic amino acids

α-Aromatic amino acid esters are important platform compound for drugs, sweeteners and fluorescent sensors. Due to the amphoteric dissociation and steric effect, the esterification of α-aromatic amino acids is difficult. Here, a green and efficient solid superacid, SO42−-S2O82−/SnO2-Nd2O3 (SSSN), was synthesized and firstly used for the methyl esterification of α-aromatic L-tyrosine and L-tryptophan. The methyl esters yield was optimized with the highest L-TyrOMe yield of 93.1% and L-TrpOMe yield of 92% over SSSN-650 (SO42−-S2O82−/SnO2-Nd2O3 calcined under 650 °C). Furthermore, it was clarified that the doping of Nd enhanced the electron-withdrawing inductive effect of SO42−/S2O82− with increased Brønsted and Lewis acidity, which were beneficial to the esterification of L-tyrosine and L-tryptophan. Besides, Nd-doping reduced the activation energy during L-Tyr esterification by kinetics study. Finally, SSSN-650 could be recycled six times with > 70% of their initial ester yield. The decrease of catalyst activity was caused by carbon deposition and species leaching. This work launched a novelty, rapid and environmental-benign technology for the esterification of α-aromatic amino acid using solid superacid.

Recent Advances in Chiral Aldehyde Catalysis for Asymmetric Functionalization of Amines

AbstractAsymmetric functionalization of amines and their derivatives is of great significance in synthetic chemistry and is widely used in the preparation of natural products and pharmaceuticals. In recent years, chiral aldehyde catalysis has emerged as a well-established and recognized tool, providing excellent catalytic activation and stereoselective control in asymmetric reactions of N-unprotected amino acid esters and amino acid ester analogues. In this short review, recent advances in enantioselective aldehyde catalysis, including chiral aldehydes as organocatalysts and co-catalysis combined with transition metals, will be summarized. Lastly, continued development of enantioselective aldehyde catalysis is prospected in the future.1 Introduction2 Chiral Aldehyde Catalysis for Tethering Strategy3 Chiral Aldehyde Catalysis for Imine Activation4 Chiral Aldehyde/Transition Metal Cooperative Catalysis5 Conclusion

Chiral aldehyde-nickel dual catalysis enables asymmetric α−propargylation of amino acids and stereodivergent synthesis of NP25302

The combined catalytic systems derived from organocatalysts and transition metals exhibit powerful activation and stereoselective-control abilities in asymmetric catalysis. This work describes a highly efficient chiral aldehyde-nickel dual catalytic system and its application for the direct asymmetric α−propargylation reaction of amino acid esters with propargylic alcohol derivatives. Various structural diversity α,α−disubstituted non-proteinogenic α−amino acid esters are produced in good-to-excellent yields and enantioselectivities. Furthermore, a stereodivergent synthesis of natural product NP25302 is achieved, and a reasonable reaction mechanism is proposed to illustrate the observed stereoselectivity based on the results of control experiments, nonlinear effect investigation, and HRMS detection.