Amino Esters Research Articles

Synthesis and Anti-Inflammatory Evaluation of a Library of Chiral Derivatives of Xanthones Conjugated with Proteinogenic Amino Acids.

In recent decades, the relationship between drug chirality and biological activity has been assuming enormous importance in medicinal chemistry. Particularly, chiral derivatives of xanthones (CDXs) have interesting biological activities, including enantioselective anti-inflammatory activity. Herein, the synthesis of a library of CDXs is described, by coupling a carboxyxanthone (1) with both enantiomers of proteinogenic amino esters as chiral building blocks (2-31), following the chiral pool strategy. The coupling reactions were performed at room temperature with good yields (from 44 to 99.9%) and very high enantiomeric purity, with most of them presenting an enantiomeric ratio close to 100%. To afford the respective amino acid derivatives (32-61), the ester group of the CDXs was hydrolyzed in mild alkaline conditions. Consequently, in this work, sixty new derivatives of CDXs were synthetized. The cytocompatibility and anti-inflammatory activity in the presence of M1 macrophages were studied for forty-four of the new synthesized CDXs. A significant decrease in the levels of a proinflammatory cytokine targeted in the treatment of several inflammatory diseases, namely interleukin 6 (IL-6), was achieved in the presence of many CDXs. The amino ester of L-tyrosine (X1AELT) was the most effective in reducing IL-6 production (52.2 ± 13.2%) by LPS-stimulated macrophages. Moreover, it was ≈1.2 times better than the D-enantiomer. Indeed, enantioselectivity was observed for the majority of the tested compounds. Thus, their evaluation as promising anti-inflammatory drugs should be considered.

Performance of Polyalkyl Acrylate Additives of Various Compositions in Low-Temperature Dewaxing of Oil Raffinates

The performance of polyalkyl acrylate additives of various compositions in low-temperature dewaxing of 11 oil fractions differing in the viscosity and content of waxes, aromatic hydrocarbons, and resins was studied. The dewaxing was performed in a methyl ethyl ketone–toluene mixed solvent. For polyalkyl acrylate with pendant C16–10 alkyl chains, the raffinates can be subdivided into three groups with respect to an increase in the yield of dewaxed oils (relative to the process without additives): increase by 12–13, 5–8, and 3–4%. In most cases, introduction into such polymer of 5–30% polar groups (amino ester, amino amide, amide, oligoethylene glycol) allowed the oil yield to be additionally increased.

A simplified viral RNA extraction method based on magnetic nanoparticles for fast and high-throughput detection of SARS-CoV-2.

The ongoing outbreak of the novel coronavirus disease 2019 (COVID-19) draws worldwide concerns due to its long incubation period and strong infectivity. Although RT-PCR-based methods are being widely applied for clinical diagnosis, timely and accurate diagnosis towards COVID-19 causing virus, the SARS-CoV-2, is still limited due to labor-intensive and time-consuming operations. Herein, we report a new viral RNA extraction method based on poly-(amino ester) with carboxyl group (PC)-coated magnetic nanoparticles (pcMNPs) for the sensitive detection of SARS-CoV-2. This method combines the lysis and binding steps into one step, and refines multiple washing steps into one step, giving a turnaround time of less than 9min. Furthermore, the extracted pcMNP-RNA complexes can be directly introduced into subsequent RT-PCR reactions without elution. This simplified viral RNA method could be well adapted in fast manual and automated high-throughput nucleic acids extraction protocols suitable for different scenarios. A high sensitivity down to 100 copies/mL and a linear correlation between 100 and 106 copies/mL of SARS-CoV-2 pseudovirus particles are achieved in both protocols. Benefitting from the simplicity and excellent performances, this new method can dramatically improve the efficiency and reduce operational requirements for the early clinical diagnosis and large-scale SARS-CoV-2 nucleic acid screening.

Effect of Bacillus subtilis and Lactobacillus plantarum on solid-state fermentation of soybean meal.

As feeding probiotics, Bacillus subtilis FJAT-4842 and Lactobacillus plantarum FJAT-13737 were employed to improve the nutritional value and reduce the risk of contamination in the solid-state fermentation of soybean meal (SBM). After fermentation with bacterium starters, the crude protein, free amino acid and lactic acid increased, with higher protease and cellulose activity. The addition of L. plantarum could increase the crude protein and lactic acid content by 50.1% and 94.9%, respectively. After fermentation, the contents of crude fiber and phytic acid decreased by 45.9% and 48.1%. Compared with control treatment, the addition of both B. subtilis FJAT-4842 and L. plantarum FJAT-13737 could effectively elevate the production of free amino acid and esters. Moreover, the addition of bacterium starter could prevent the production of mycotoxin and promote bacterial diversity of the fermented SBM. Especially, the addition of B. subtilis could reduce the relative content of Staphylococcus. After fermentation for 7 days, lactic acid bacteria including Pediococcus, Weissella and Lactobacillus became the main bacteria in the fermented SBM. The addition of bacterium starter is of benefit with respect to improving the nutritional value and reducing the risk of contamination in the solid-state fermentation of soybean. © 2023 Society of Chemical Industry.

Total turnover number prediction of an aggregating biocatalyst: Amino ester hydrolase (AEH)

Amino ester hydrolase (AEH) from Xanthomonas campestris is a promising candidate for β-lactam synthesis but suffers from low thermostability and rapid deactivation. Wild-type AEH was found to deactivate with an apparent order that varies with temperature from n = 2 at 30 °C (close to the temperature of optimum activity Topt) to n = 1.5 at 25 °C. AEH features two transitional temperatures: (1) from native ‘N’ to partially unfolded, inactive intermediate ‘I’, and (2) from partially unfolded to fully unfolded entity ‘U’ at the melting temperature Tm. CD and light scattering data suggest aggregation near Topt. To determine the total turnover number TTN, AEH was deactivated by imposing a temperature gradient and recording instantaneous rates of cephalexin hydrolysis. The TTN increased ∼ 5-fold from the wild-type (WT) for the quadruple variant N186D/A275P/E143H/V622I (QVH) at 25 °C and 10 nM AEH but varied significantly with AEH concentration and temperature.

Engineering brain-derived neurotrophic factor mRNA delivery for the treatment of Alzheimer’s disease

Brain-derived neurotrophic factor (BDNF) has a long history in the treatment neurodegenerative of diseases. However, this therapy has limitations in exogenous protein safety, including side effects like neuropathic pain and seizures. Moreover, there are currently no positive clinical trial results using BDNF-based gene therapy. Given this, new methods of delivering BDNF are urgently needed. Here, we report an engineering BDNF mRNA-based therapy in a murine model of Alzheimer’s disease (AD). Two poly (β amino esters) polymers (PBAE) were synthesized, which achieved mRNA delivery to brain and spinal cord efficiently following catheter ventricle pumping. To confer stability and RNase resistance, the secondary structure of the mRNA was engineering using AI algorithms. Further mRNA modification was done on 3′ untranslated region (3′UTR), which was added with neuron-specific miRNA targeting sequence to avoid BDNF protein expression in neuron. This allowed reduced neuronal overexcitation and seizures. And BDNF protein was sustained released from astrocytes to maintain surrounding neural function. The engineering mRNA was delivered into the brain ventricle and translated into astrocytes to significantly improve the memory of AD mice. Given the mRNA modifications presented here, it would de-target delivery to specific cell types and has therapeutic potential for the treatment of neurological diseases.

Highly Stereoselective Synthesis of γ,δ‐Unsaturated Quaternary α‐Amino Esters via the Tandem N‐Alkylation/Claisen Rearrangement of α‐Imino Allylesters

Abstractγ,δ‐Unsaturated amino acids are the backbone of various natural products and pharmaceuticals, while quaternary α‐amino acids are also powerful enzyme inhibitors, and both are very important compounds in bioorganic chemistry. A highly efficient synthesis of γ,δ‐unsaturated quaternary amino esters utilizing the tandem umpolung/Claisen rearrangement for α‐iminoallyl esters was developed. This method has a wide range of substrates taking account of the Hammett rule, and highly stereoselective Claisen rearrangement were achieved by the effect of DMSO or the ortho‐substituents of imino carbon. Furthermore, product functionalization also showed the usefulness of this reaction and the detailed reaction mechanism was elucidated from isotopic labeling experiments, kinetic isotope effects and crossover‐experiments.

Antibacterial and pH-sensitive methacrylate poly-L-Arginine/poly (β-amino ester) polymer for soft tissue engineering

During the last decade, pH-sensitive biomaterials containing antibacterial agents have grown exponentially in soft tissue engineering. The aim of this study is to synthesize a biodegradable pH sensitive and antibacterial hydrogel with adjustable mechanical and physical properties for soft tissue engineering. This biodegradable copolymer hydrogel was made of Poly-L-Arginine methacrylate (Poly-L-ArgMA) and different poly (β- amino ester) (PβAE) polymers. PβAE was prepared with four different diacrylate/diamine monomers including; 1.1:1 (PβAE1), 1.5:1 (PβAE1.5), 2:1 (PβAE2), and 3:1 (PβAE3), which was UV cross-linked using dimethoxy phenyl-acetophenone agent. These PβAE were then used for preparation of Poly-L-ArgMA/PβAE polymers and revealed a tunable swelling ratio, depending on the pH conditions. Noticeably, the swelling ratio increased by 1.5 times when the pH decreased from 7.4 to 5.6 in the Poly-L-ArgMA/PβAE1.5 sample. Also, the controllable degradation rate and different mechanical properties were obtained, depending on the PβAE monomer ratio. Noticeably, the tensile strength of the PβAE hydrogel increased from 0.10 ± 0.04 MPa to 2.42 ± 0.3 MPa, when the acrylate/diamine monomer molar ratio increased from 1.1:1 to 3:1. In addition, Poly-L-ArgMA/PβAE samples significantly improved L929 cell viability, attachment and proliferation. Poly-L-ArgMA also enhanced the antibacterial activities of PβAE against both Escherichia coli (~5.1 times) and Staphylococcus aureus (~2.7 times). In summary, the antibacterial and pH-sensitive Poly-L-ArgMA/PβAE1.5 with suitable mechanical, degradation and biological properties could be an appropriate candidate for soft tissue engineering, specifically wound healing applications.Graphical

Visible-light-mediated catalytic asymmetric synthesis of α-amino esters via free carbene insertion into N[sbnd]H bond

A method that facilitates the construction of valuable chiral products exploiting simple high energy intermediates in an atom- and sustainable fashion could prove highly enabling for asymmetric synthesis. Free carbenes are one kind of such high energy intermediates and their utilization in catalytic asymmetric reactions is still elusive, due to the existence of severe racemic background reaction. In our pursuit to develop catalytic asymmetric NH insertion reaction of free carbene, a general chiral Brønsted acid-catalyzed enantioselective protonation of the in situ generated ammonium ylide was discovered under visible-light irradiation of diazo compound in the presence of arylamine, furnishing the desired α -amino esters with moderate to high enantioselectivity and yield. More importantly, it was found there is a remarkable correlation between the enantioselectivity of product and substituent electronic parameter (σpara) of substrates. This work not only demonstrates chiral phosphoric acid catalysis is compatible with free carbene insertion reactions without disturbing deactivation OH insertion side reactions, but also indicates the pKa of arylamine is also a significant parameter for turning the enantioselectivity of the reaction. The method disclosed herein is expected to bring new insights into the use of free carbene in the catalytic asymmetric reactions under metal free conditions.

Characterizing the Impact of Package Type on Beer Stability

The brewing industry is highly competitive, driving the importance of beer stability. Brewers use both aluminum cans and glass bottles to distribute products; however, a direct comparison of the impact of these two package types on beer stability has yet to be conducted. Here, a non-targeted metabolomics approach was used to characterize changes in the metabolite profile of amber ale (AA) and India pale ale (IPA) packaged in cans and bottles over a 6-month aging period. A strong correlation by package type was observed for AA but not for IPA over all time points. Baseline differences in amino acids (glycine, tyrosine, and asparagine) and esters (isobutyl isobutyrate, 2-methylbutyl butyrate, and ethyl decanoate) were also observed in AA. Hop terpenes (humulene, pinocarvone, and α-calacorene) demonstrated package-dependent changes over time which appear to be influenced by metabolite water solubility. Overall, the results demonstrate that beer metabolites, and thus stability, are significantly impacted by package type.

Microbial communities and metabolite profiles during the fermentation of Chinese Dongbei suancai with Chinese baijiu as supplementary material.

In industrial production of suancai, baijiu is commonly used to inhibit the spoilage bacteria and enhance the flavor. However, the effects of baijiu on the microbial diversity and metabolic pathways of suancai are rarely reported in the literature. This study aimed to explore the microbial community, its predicted functional roles, and the metabolites formed during fermentation of Chinese Dongbei suancai fermented using a mixed starter with Chinese baijiu as supplementary material. Results showed that Lactobacillus, Enterobacter, and Leuconostoc were the major bacterial genera in the Dongbei suancai fermented by adding baijiu. Linear discriminant analysis effect size indicated that Leuconostoc was the major biomarker in the early stage of fermentation, whereas Lactococcus, Weissella, and Lactobacillus plantarum were biomarkers in the middle and later stages of fermentation. A total of 638 metabolites were detected in suancai fermented by adding baijiu. However, the principal component analysis showed that baijiu significantly affected the metabolites of suancai in the early and later stages of fermentation. Furthermore, 58, 22, and 26 significantly differential metabolites (P < 0.01) were found on day0, day2, and day 30 of fermentation respectively. Moreover, Lactobacillus, Lactococcus, and Enterobacter had positive correlations with amino acids, nucleotides, organic acids, alcohols, and esters. Functional analysis implied that carbohydrate, amino acid, energy, and nucleotide metabolism were the major determinants of the characteristics of suancai fermented with baijiu as supplementary material. Baijiu changed the metabolites of inoculated fermented Dongbei suancai. © 2023 Society of Chemical Industry.

Recent progress and applications of poly(beta amino esters)-based biomaterials.

Poly(beta-amino esters, PBAEs) are a promising class of cationic polymers synthesized from diacrylates and amines via Michael addition. Recently, PBAEs have been widely developed for drug delivery, immunotherapy, gene therapy, antibacterial, tissue engineering and other applications due to their convenient synthesis, good bio-compatibility and degradation properties. Herein, we mainly summarize the recent progress in the PBAEs synthesis and their applications. The amine groups of PBAEs could be protonated in low pH environment, exhibiting proton sponge and pH-sensitive abilities. Furthermore, the positive PBAEs can interact with negative genes via electrostatic interactions for efficient delivery of nucleic acids. Moreover, positive PBAEs could also directly kill bacteria by disrupting their membranes at high doses. Finally, PBAEs can augment the immune responses, and improve the bioactivity of hydrogels in tissue engineering.

Design synthesis and biological evaluation of thiophene 2- pentafluoro benzamide derivatives as antitubercular agent

Tuberculosis, a major contagious air-borne disease, killing millions in a year. Many of the existing anti-tubercular drugs have acquired bacterial resistance. Though they are highly bactericidal but, later on due to several factors like poor patient compliance, incomplete therapy, etc. leading to treatment relapse. This enables researcher to focus on identifying new leads utilizing structure-based drug design which plays a crucial role in drug development. The mycolic acid synthesized by Pks 13 is identified as a perfect target and hence a series of molecules were designed and the best fit ligands with a least energy were picked and analysed for Insilco bioactivity and drug likeness. Five best docked Molecules satisfied the Lipinski rule of five, namely the number of hydrogen bond donors, acceptors, log P, total polar surface area and the number of rotatable bonds. The bioactivity was found to be moderate to excellent against the receptor. The target molecules were synthesised via amino esters to yield pentafluorinated thiophene derivatives. Among the series, molecule 12 was found to be more potent when tested for antitubercular activity by Microplate Alomar blue assay technique.

Comprehensive investigation on volatile and non-volatile metabolites in low-salt doubanjiang with different fermentation methods

Doubanjiang is a well-known fermented condiment in China, but the high-salt concentration in its traditional manufacture process greatly lengthens the fermentation time, and leads to potential health risks. Here, the effects of salt reduction and co-inoculated starters (Tetragenococcus halophilus and Zygosaccharomyces rouxii) on the volatile metabolites (VMs) and non-volatile metabolites (NVMs) of doubanjiang were investigated using metabolomics technology and chemometrics analysis. Results showed that 75 VMs were identified, and 12 of them had significant aroma contribution (ROVAs ≥ 1). In addition, 106 NVMs were defined as significantly different metabolites (p < 0.05; VIP ≥ 1). Salt reduction could significantly increase the concentrations of VMs, but this strategy also promoted some undesirable odors like 2-phetylfuran and hexanoic acid, which could be totally suppressed by inoculation of starter. Moreover, the two starters improved amino acid, ester, and acid metabolites. This study provides a deeper insight into the development of low-salt fermented foods.

Laboratory Scale Continuous Flow Systems for the Enantioselective Phase Transfer Catalytic Synthesis of Quaternary Amino Acids.

The use of stereoselective phase-transfer catalysis as a reliable method for the enantioselective synthesis of optically active α-amino acid derivatives using achiral Schiff base esters has been well-developed in batch in the last 40 years. Recently, continuous flow technology has become of great interest in the academy and industry, since it offers safer process operating conditions and higher efficiency compared to a traditional batch processing. Herein, we wish to report the first example of enantioselective phase transfer benzylation of alanine Schiff base ester, under continuous flow conditions. Two different methodologies were investigated: a liquid-solid phase transfer catalytic benzylation using a packed-bed reactor and a liquid-liquid phase transfer catalytic benzylation in continuous stirred-tank reactors. Liquid-liquid phase transfer process in flow showed slightly better productivity than the batch process, while solid-liquid phase transfer benzylation proved much more advantageous in terms of productivity and space-time yield. Furthermore, continuous flow system allowed the isolation of benzylated product without any work up, with a significant simplification of the process. In both cases, phase transfer asymmetric benzylation promoted by Maruoka catalyst demonstrated high enantioselectivity of target quaternary amino ester in flow, up to 93% ee.

Hybrid Phosphine/Amino-Acid Ligands Built on Phenyl and Ferrocenyl Platforms: Application in the Suzuki Coupling of o-Dibromobenzene with Fluorophenylboronic Acid.

We describe the synthesis and characterization of two classes of hybrid phosphino ligands functionalized with amino ester or amino acid groups. These compounds are built either on a rigid planar phenyl platform or on a functionalized - conformationally controlled - rotational ferrocene backbone. Modifications at the -PR2 phosphino groups (R=aryl and alkyl, with various steric bulk, Ph, Mes, i-Pr, Cy) and at the amino acid/amino ester functions are reported, showing a valuable high modularity. The coordination chemistry of these compounds regarding palladium and gold was investigated, in particular with respect to the coordination mode of the phosphino groups and the preferred interaction with metals for the amino ester and amino acid functions. For all the hybrid ligands, based either on ferrocenyl or phenyl platforms, the (P,N)-chelating effect dominates in solution for coordination to Pd(II), while linear P-Au(I) complexes without interaction with the amino groups are assumed. The investigation of the catalytic activity of these new ligands in the demanding palladium-catalyzed Suzuki-Miyaura coupling of o-dibromoarenes with fluorophenylboronic acid underlined the importance of the amino ester dicyclohexylphosphinoferrocene for avoiding the deleterious homocoupling and arene oligomerization side-reactions that were otherwise observed with the other phosphine ligands.

Mechanistic explorations on the decarboxylative allylation of amino esters via dual photoredox and palladium catalysis.

Mechanistic studies reveal that the decarboxylative allylation of amino esters via dual photoredox and palladium catalysis occurs via oxidation giving π-allyl-Pd(II) species and carboxylate, which is oxidized by *Ir(III)-catalyst offering benzyl radicals. The alkylated product is formed via an SN2 pathway. Single-electron transfer between Pd(I)-species and Ir(II)-catalysis restores both catalysts.

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.

Stereocontrolled synthesis of some novel functionalized heterocyclic amino ester and amide derivatives with multiple stereocenters.

The synthesis of some novel functionalized fused-ring β-amino lactones and lactams with multiple chiral centers has been attempted from readily available strained bicyclic β-amino acids via a stereocontrolled synthetic route. The key step was ring-rearrangement metathesis of allyl/propargyl esters or N-allylated/N-propargylated amides of (oxa)norbornene β-amino acids. The RRM transformations [ring-opening metathesis (ROM)/ring-closing metathesis (RCM) or ring-opening metathesis (ROM)/ring-closing enyne metathesis (RCEYM)] have been investigated using some commercially available catalysts. Importantly, the procedure used in this synthetic process does not affect the configurations of the chiral centers. This means that the structure of the starting (oxa)norbornene β-amino acids predetermines the configuration of the formed products.

Poly (beta-amino ester) as an in vivo nanocarrier for therapeutic nucleic acids.

Therapeutic nucleic acids are an emerging class of therapy for treating various diseases through immunomodulation, protein replacement, gene editing, and genetic engineering. However, they need a vector to effectively and safely reach the target cells. Most gene and cell therapies rely on ex vivo gene delivery, which is laborious, time-consuming, and costly; therefore, devising a systematic vector for effective and safe in vivo delivery of therapeutic nucleic acids is required to target the cells of interest in an efficient manner. Synthetic nanoparticle vector poly beta amino ester(PBAE), a class of degradable polymer, is a promising candidate for in vivo gene delivery. PBAE is considered the most potent in vivo vector due to its excellent transfection performance and biodegradability. PBAE nanoparticles showed tunable charge density, diverse structural characteristics, excellent encapsulation capacity, high stability, stimuli-responsive release, site-specific delivery, potent binding to nucleic acids, flexible binding ability to various conjugates, and effective endosomal escape. These unique properties of PBAE are an essential contribution to in vivo gene delivery. The current review discusses each of the components used for PBAE synthesis and the impact of various environmental and physicochemical factors of the body on PBAE nanocarrier.