Simple Esters Research Articles

Mammalian Esterase Activity: Implications for Peptide Prodrugs.

As a traceless, bioreversible modification, the esterification of carboxyl groups in peptides and proteins has the potential to increase their clinical utility. An impediment is the lack of strategies to quantify esterase-catalyzed hydrolysis rates for esters in esterified biologics. We have developed a continuous Förster resonance energy transfer (FRET) assay for esterase activity based on a peptidic substrate and a protease, Glu-C, that cleaves a glutamyl peptide bond only if the glutamyl side chain is a free acid. Using pig liver esterase (PLE) and human carboxylesterases, we validated the assay with substrates containing simple esters (e.g., ethyl) and esters designed to be released by self-immolation upon quinone methide elimination. We found that simple esters were not cleaved by esterases, likely for steric reasons. To account for the relatively low rate of quinone methide elimination, we extended the mathematics of the traditional Michaelis-Menten model to conclude with a first-order intermediate decay step. By exploring two regimes of our substrate → intermediate → product (SIP) model, we evaluated the rate constants for the PLE-catalyzed cleavage of an ester on a glutamyl side chain (kcat/KM = 1.63 × 103 M-1 s-1) and subsequent spontaneous quinone methide elimination to regenerate the unmodified peptide (kI = 0.00325 s-1; t1/2 = 3.55 min). The detection of esterase activity was also feasible in the human intestinal S9 fraction. Our assay and SIP model increase the understanding of the release kinetics of esterified biologics and facilitate the rational design of efficacious peptide prodrugs.

Preparation and Preclinical Characterization of a Simple Ester for Dual Exogenous Supply of Lactate and Beta-hydroxybutyrate.

Elevation of the plasma levels of (S)-lactate (Lac) and/or (R)-beta-hydroxybutyrate (BHB) occurs naturally in response to strenuous exercise and prolonged fasting, respectively, resulting in millimolar concentrations of these two metabolites. It is increasingly appreciated that Lac and BHB have wide-ranging beneficial physiological effects, suggesting that novel nutritional solutions, compatible with high-level and/or sustained consumption, which allow direct control of plasma levels of Lac and BHB, are of strong interest. In this study, we present a molecular hybrid between (S)-lactate and the BHB-precursor (R)-1,3-butanediol in the form of a simple ester referred to as LaKe. We show that LaKe can be readily prepared on the kilogram scale and undergoes rapid hydrolytic conversion under a variety of physiological conditions to release its two constituents. Oral ingestion of LaKe, in rats, resulted in dose-dependent elevation of plasma levels of Lac and BHB triggering expected physiological responses such as reduced lipolysis and elevation of the appetite-suppressing compound N-L-lactoyl-phenylalanine (Lac-Phe).

Nucleophilic Aromatic Substitution of Heteroaryl Halides with Thiols.

The nucleophilic aromatic substitution (SNAr) between heteroaryl halides (Cl, Br) and thiols proceeds smoothly in DMAc under the action of K2CO3 at rt-100 °C. For most electron-deficient heteroarenes, reaction takes place without introducing an additional electron-withdrawing group. For electron-rich heteroarenes, an additional electron-withdrawing group such as a simple ester, keto, cyano, and nitro group is required to ensure the reaction completes. The reactivity trend of heteroaryl halides is highly dependent on the electronic nature of the heteroarenes and orientation of halogens. Besides thiols, a couple of functionalized thioureas and thioamides are compatible with these conditions, providing the corresponding heteroaryl thioethers in good yields.

Acid-Mediated Domino Cyclization of ortho-Formyl Cinnamate Esters: Synthesis of Substituted Indene/Indane Esters and Indeno[a]indenones.

A Bro̷nsted acid-driven protocol to access substituted monoarylindene esters, biarylindane esters, and indeno[a]indenones from simple ortho-formylcinnamate esters and external arenes has been revealed. Remarkably, this single-pot process enabled the construction of two, three, and four new C-C bonds in building monoarylindene esters, biarylindane esters, and indeno[a]indenones, respectively, under metal-free and mild reaction parameters via triggering the inactive cinnamate ester moiety. In addition, the present strategy is investigated with widespread substrate scope.

Development of Catalytic Enantioselective Mannich Reactions Using Esters.

Catalytic enantioselective Mannich reactions of simple nonactivated esters proceeded using a chiral potassium strong base catalyst prepared from a chiral bisoxazoline and potassium hexamethyldisilazide. Alkyl acetates, alkyl propionates, and an alkyl butyrate were employed as the simple esters, and the desired reactions proceeded smoothly to afford Mannich products in good to high yields with high enantioselectivities. One of the products was successfully employed in the asymmetric total synthesis of Maraviroc.

Divergent Synthesis of Fluoroalkyl Ketones through Controlling the Reactivity of Organoboronate Complexes.

Herein, we report a divergent synthesis of fluoroalkyl ketones through visible-light-induced reactions between readily available organoboronic esters and fluoroalkyl acylsilanes. Selective control of the reactivity of the in situ generated organoboronate complexes is the key to achieving divergent transformations. Under basic conditions, the organoboronate complexes undergo deboronative fluoride elimination, resulting in the formation of enol silyl ethers as intermediates that react with various electrophiles to generate defluorinated ketones as the products. Moreover, in combination with peroxide, a 1,2-shift of fluoroalkyl group is favored over deboronative fluoride elimination to generate ketal intermediates, leading to the formation of ketones as the products. This transition-metal-free reaction is operationally simple, and aryl, alkenyl, and alkyl boronic esters are all suitable substrates. The synthetic potential has been demonstrated by gram-scale reactions and facile synthesis of bioactive molecules including zifrosilone and its fluoroalkyl analogs.

Ethyl pyruvate attenuates cerebral hypoxia/reoxygenation injury in neuroblastoma cells: Role of GAS6/Axl signaling

BackgroundIschemic stroke, caused neurological dysfunction due to inadequate blood supply to brain, has a high morbidity and mortality. Ethyl pyruvate (EP), a simple aliphatic ester derived from pyruvic acid, has the advantages of safety and stability. Studies have confirmed that EP has anti-oxidative, anti-inflammation, anti-tumor, and other pharmacological effects, and it demonstrates significant therapeutic effects on multiple diseases. GAS6 and its high affinity Axl receptor play an important role in cell adhesion, anti-apoptosis, proliferation and migration by activating downstream signal transduction pathways. Previous studies have demonstrated the neuroprotective effects of the GAS6/Axl axis. MethodsA series of experimental methods were employed to confirm the effect of EP against cerebral hypoxia/reoxygenation (HR) injury. ResultsIn this study, the protective effect and mechanism of EP on HR injury in N2a cells was explored. The results found that treatment with EP could increase HR-injured neuronal viability, improve cell morphology, and reduce LDH release and ROS accumulation, thereby exhibiting a neuroprotective effect. Furthermore, EP treatment restored the down-regulated expression of GAS6, Axl, NQO1, PGC-1α, NRF1, and UCP2 caused by HR injury. Specifically, it was observed that the neuroprotective effect of EP was partially inhibited by GAS6 siRNA. ConclusionIn conclusion, these results suggest that EP treatment attenuates HR-induced oxidative stress injury in neuroblastoma cells via activating GAS6/Axl signaling.

Effectiveness of methyl tert-butyl ether and ethynylcyclohexanol on increasing the octane number of gasoline compositions of straightrun gasoline + reforming

One of the ways to expand the production of high-octane unleaded gasoline is the use of oxygen-containing components (oxygenates). The addition of oxygenates increases the detonation resistance, especially of light fractions, the completeness of gasoline combustion, reduces fuel consumption and reduces the toxicity of exhaust gases. It was found that such an amount of oxygenates, despite their lower calorific value compared to gasoline, does not adversely affect the energy performance of engines. Oxygen-containing additives are complex and simple esters of monocarboxylic acids, higher alcohols, oxidized hydrocarbon fractions containing mixtures of acids, alcohols and esters, and oxyethylated compounds. Because of its high octane number, which allows the compression ratio to be increased to 16, methanol is used to fuel racing motorcycles and cars.The effect of ethynylcyclohexanol (ECH) and methyl tret-butyl ether (MTBE) on increasing the octane number of gasoline compositions has been evaluated by increasing the octane number of a 50:50 and 20:80 mixture of straight-run gasoline and reforming gasoline. It has been shown that ECH is an effective oxygen-containing additive (oxygenate) for increasing the octane number of gasoline compositions, compared with MTBE.

Sensory dimensions derived from competitive and creative perceptual interactions between fruity ethyl esters and woody odorants in wine-like models

The present study analyses the sensory effects associated with the interactions between different woody aroma compositions and a simple fruity ester vector in red wines. The semi-synthetic wine models contained a fixed aroma composition, the dearomatised non-volatile fraction of red wine and 21 different combinations of ethyl 2-methylbutyrate (fruity vector) plus 1 out of 3 woody aroma compositions (woody vectors) at 3 possible levels of concentration each. Woody vectors imitated a highly toasted American oak (HAO—elevated levels of whiskylactones and furaneol), a highly toasted French oak (HFO—low levels of whiskylactone and vanillin levels, high levels of eugenol and guaiacol) and a medium toasted French oak (MFO—low levels of whiskylactones, eugenol, guaiacol and furaneol and high levels of vanilla). Models were sensorily assessed by a sorting task and by descriptive analysis. The increase in woody notes causes a concomitant decrease in fruity notes by a competitive perceptual interaction. HAO models are richest in coconut and woody notes and poorest in fruity notes, while HFO models keep strawberry and apple notes. At certain specific fruity-woody vector ratios, particularly in the MFO model, blackcurrant notes emerge, which can be considered a creative perceptual interaction.

Microwave-Accelerated McKenna Synthesis of Phosphonic Acids: An Investigation.

Phosphonic acids represent one of the most important categories of organophosphorus compounds, with myriad examples found in chemical biology, medicine, materials, and other domains. Phosphonic acids are rapidly and conveniently prepared from their simple dialkyl esters by silyldealkylation with bromotrimethylsilane (BTMS), followed by desilylation upon contact with water or methanol. Introduced originally by McKenna, the BTMS route to phosphonic acids has long been a favored method due to its convenience, high yields, very mild conditions, and chemoselectivity. We systematically investigated microwave irradiation as a means to accelerate the BTMS silyldealkylations (MW-BTMS) of a series of dialkyl methylphosphonates with respect to solvent polarity (ACN, dioxane, neat BTMS, DMF, and sulfolane), alkyl group (Me, Et, and iPr), electron-withdrawing P-substitution, and phosphonate-carboxylate triester chemoselectivity. Control reactions were performed using conventional heating. We also applied MW-BTMS to the preparation of three acyclic nucleoside phosphonates (ANPs, an important class of antiviral and anticancer drugs), which were reported to undergo partial nucleoside degradation under MW hydrolysis with HCl at 130-140 °C (MW-HCl, a proposed alternative to BTMS). In all cases, MW-BTMS dramatically accelerated quantitative silyldealkylation compared to BTMS with conventional heating and was highly chemoselective, confirming it to be an important enhancement of the conventional BTMS method with significant advantages over the MW-HCl method.

Toxicity of organophosphorus flame retardants

As the development and use of organophosphorus flame retardants have become more prevalent, concerns about potential toxicity are being raised. To date, most studies on potential toxicity have focused on simple phosphate esters and often include both alkyl and aryl esters or, in some cases, even halogenated phosphate esters (which should more properly be included among organohalogen flame retardants). The inclusion of several kinds of esters into a single study leads to muddled conclusions. Each class of phosphate esters should be subjected to toxicity assessment separately. Furthermore, the potential toxicity of the more effective (lower level of oxygenation at phosphorus: phosphonates, phosphinates, phosphine oxides) organophosphorus flame retardants has been little explored. The few results available suggest that these compounds exhibit no or minimal toxicity (lower than that of phosphates?). This represents an area that should be the focus of careful detailed studies to establish any potential toxicity.

A Catalytic Method for the Enantioselective Synthesis of α‐Quaternary Ketones, α‐Ketoesters and Aldehydes

AbstractA practical method for the efficient and enantioselective preparation of versatile ketones and aldehydes that contain an α‐quaternary stereocenter is described. Reactions utilize simple carboxylic acid or ester starting materials, a monodentate chiral phosphine, and afford a variety of aryl, alkenyl, alkynyl, and alkyl‐substituted ketone and aldehyde products in 25–94 % yield and 90 : 10 to >99 : 1 enantiomeric ratio. Reactions proceed by acyl substitution with in situ formed chiral allylic nucleophiles, and display selectivity and conversion dependence on a protic additive. The utility of the approach is demonstrated through several product transformations.

A Catalytic Method for the Enantioselective Synthesis of α-Quaternary Ketones, α-Ketoesters and Aldehydes.

A practical method for the efficient and enantioselective preparation of versatile ketones and aldehydes that contain an α-quaternary stereocenter is described. Reactions utilize simple carboxylic acid or ester starting materials, a monodentate chiral phosphine, and afford a variety of aryl, alkenyl, alkynyl, and alkyl-substituted ketone and aldehyde products in 25-94 % yield and 90 : 10 to >99 : 1 enantiomeric ratio. Reactions proceed by acyl substitution with in situ formed chiral allylic nucleophiles, and display selectivity and conversion dependence on a protic additive. The utility of the approach is demonstrated through several product transformations.

Ortho‐Quinols in (Bio)Synthesis of Natural Products

Abstract6‐Alkyl‐6‐hydroxycyclohexa‐2,4‐dienone derivatives, commonly referred to as ortho‐quinols, and their simple ester and ether variants constitute a class of organic compounds that aroused much interest amongst chemists over the past 70 years for several reasons related to organic synthesis, natural product chemistry and biochemistry. It was very early on that organic chemists understood the potential of the unique yet versatile chemical reactivity of such compounds to synthesize more complex structures, and it soon emerged that ortho‐quinols could constitute key intermediates in the biosynthesis of certain natural products of various origins. This minireview discusses the chemistry of ortho‐quinols from the point of view of their role in the synthesis and biosynthesis of natural products. Examples of completed syntheses of natural products mostly taken in the literature of the last 20 years or so, together with some chosen pieces from older but pioneering and most remarkable works, are highlighted to illustrate this discussion.

Visible-light-induced aerobic epoxidation with vitamin B2-based photocatalyst.

Herein we described the catalytic epoxidation of α,β-enone, with peroxide in situ generated, via a predominant single electron transfer and a minor energy transfer pathway. We use inexpensive natural vitamin B2 (riboflavin, RF) or its simple ester (riboflavin tetraacetate, RFT) as the photocatalysts, commonly used 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) as both the electron source and organic base, and ambient air as the terminal oxidant, under visible-light irradiation and room temperature.

In vivo polymerization of the dopamine-borate melanin precursor: A proof-of-concept regarding boron neutron-capture therapy for melanoma

The 10boron neutron-capture therapy (BNCT) is an emerging antitumoral method that shows increasing biomedical interest. BNCT is based on the selective accumulation of the 10boron isotope within the tumor, which is then irradiated with low-energy thermal neutrons, generating nuclear fission that produces 7lithium, 4helium, and γ rays. Simple catechol-borate esters have been rather overlooked as precursors of melanin biosynthesis, and therefore, a proof-of-concept approach for using dopamine-borate (DABO) as a suitable boron-containing candidate for potential BNCT is presented here. DABO can spontaneously oxidize and autopolymerize in vitro, giving a soluble, eumelanin-like brown-black poly-DABO product. Melanotic melanoma cell cultures treated with 1 mM DABO for 24 and 48 h were viable and showed no signs of damage or cell death. The stability and possible trans-esterification of DABO is shortly discussed. Chemical calculations and quantitative structure-activity relationships (QSAR) analysis of DABO and the BNCT agent BPA indicated that they should be cell permeant and accumulate within lysosomes and melanosomes. Molecular modeling allows visualization of both the DABO precursor and the structure of a borate derivative of the proposed catechol-porphycene model for eumelanin, showing interesting features from molecular orbital calculations. The main difference between DABO and other agents, such as BPA, is that it is not a boronic acid nor a boron cluster. This simple catechol-borate ester (protected from oxidation and blackening) could be administrated to living cells and organisms, in which biosynthesis of boron-melanin in melanoma melanocytes can lead to improved BNCT.

THE INFLUENCE OF CHITOSANES ON THE DYNAMICS OF THE CONTENT OF PHENOLIC COMPOUNDS IN TOMATO LEAVES

The aim of this work was to study the influence of chitosans of different molecular weight on the dynamics of the content of phenolic compounds in tomato plants of the 'Zagadka' variety. In the experiment, tomato plants treated with chitosan with a molecular weight of 50-190 kDa and 310-375 kDa were studied. Using the method of high-performance thin-layer chromatography (HPTLC), biochemical profiling of the extracts of the studied plants was performed. Differences in the primary reactions of plants to chitosans of different molecular weights were revealed. Low molecular chitosan caused a significant increase in the content of phenols and, accordingly, increased the antioxidant potential of leaf tissues. The increase in the content of phenols in response to the action of low-molecular-weight chitosan occurs due to the activation of phenylpropanoid synthesis and an increase in the total antioxidant potential, which indicates the mobilization of the plant organism against a potential pathogen. Thus, an hour after the treatment of plants with a solution of low molecular weight chitosan, the content of rutin in the leaves was 3.36 mg/g, and after 18 hours - 5.56 mg/g. The content of chlorogenic and caffeic acids in the leaves increased in 12 hours. In 18 hours, the content of chlorogenic acid was 1.64 mg/g, and caffeic acid was 0.18 mg/g. This may be due to the gradual decomposition of chlorogenic acid into its constituent components under the influence of low molecular weight chitosan, which is accompanied by the release of caffeic acid. A positive correlation was established between the pool of chlorogenic and caffeic acid (r = 0.995; p < 0.06). Therefore, depending on the molecular weight, chitosan causes significant changes in the synthesis of phenylpropanoids and biochemical transformation of complex and simple esters of hydroxycinnamic acids in tomato plants. The high-molecular chitosan solution caused a decrease in the number of compounds with high antioxidant potential in tomato leaves, which indicates the activation of another plant defense system. The content of rutin in leaves treated with high-molecular-weight chitosan after 18 hours was 1.32 mg/g, which is four times less compared to the treatment of plants with low-molecular-weight chitosan. At the same time, in response to treatment with high molecular weight chitosan, the content of caffeic acid in the leaves increased significantly. The decrease in the content of phenols is associated with the isolation of tissues from a potential threat, which is aimed at its neutralization. The result of such a reaction is the oxidation of phenolic compounds, additional lignification and suberinization of cell walls. The activation of various induced immunity reactions in the plant organism already in the first hours after eating low-molecular or high-molecular chitosan indicates the existence of a system of differential recognition of complex bipolymers by plants.

Extraction of cellulose from paulownia plants and its simple ester carboxymethyl cellulose (na-kms) technology

In this experiment, Paulownia fiber plant is ground to 0.5-1 cm. In order to determine the optimum alkali solution concentration to extract cellulose from the raw material, the optimum degree of polymerization was determined by boiling in 25, 35, 50, 55 g/l solution. It can be seen from the table that certain properties of cellulose produced under the influence of different concentrations of alkali have different indicators. At alkaline concentration of 50 g/l, the cellulose yield was 49.6%, α-cellulose 89.5%, and the degree of polymerization was known in 1100 experiments. Ash content was a positive indicator of 1.78%. The scientific essence is that the cellulose is first soaked in isopropyl alcohol and mercerized in caustic alkali (NaOH) solution. Then, the alkylation process is carried out by adding a certain amount of monochloroacetic acid to the alkaline cellulose. Then, the alkylation process is carried out by adding a certain amount of monochloroacetic acid to the alkaline cellulose. The resulting carboxymethylcellulose is sent for purification. Na-CMC with 38-40% moisture content is washed in 53% ethyl alcohol and dried.

Supramolecular Architecture of an Amphiphilic Amino Alcohol as a Versatile Chiral Environment for Stereocontrolled Photoreaction of Various Anthracenes.

The photocyclodimerization of 2-anthracenecarboxylic acid has been extensively studied as a model reaction of asymmetric photochemistry. So far, numerous chiral environments have been employed to control this photoreaction, while the scope of photoreactants has been limited only to 2-anthracenecarboxylic acid and its simple esters and amides. Here, we developed a systematic series of photoreactants (2 a-d) by introducing various substituents to 2-anthracenecarboxylic acid, which showed different reactivities and selectivities depending on the substituents. By using the photoreactants 2 a-d, we evaluated the performance of a chiral environment composed of an amphiphilic amino alcohol (1), where the photocyclodimerization of 2 a-d generally proceeded in excellent regio- and enantioselectivities (71-98 % regio ratio, 76-86 % ee). Furthermore, by reacting 2 a and 2 b together in the chiral environment of 1, we succeeded in the first stereocontrolled cross-photocyclodimerization between two prochiral anthracenes (58 % chemo ratio, 83 % regio ratio, 90 % ee).

Similar structural complexity of phenols in plant morphotypes with contrasting soluble phenol concentration and richness in arid rangelands of Patagonia

Phenols can play a significant role in plant tolerance of drought and herbivory. We assessed the concentration, richness and structural complexity of soluble phenols (hereafter phenols) in leaves of different species representing different plant morphotypes of arid ecosystems. We selected seven species representative of the three main plant morphotypes of the Patagonia Monte (Argentina): tall evergreen shrubs (TES), medium evergreen shrubs (MES), and perennial grasses (PG). These morphotypes differed in plant height, rooting depth, proportion of photosynthetic tissues, specific leaf area, and concentration of phenols and N in leaves. We found 48 compounds belonging to six types of phenols differing in structural complexity (low complexity: simple phenols, phenolic acids and phenolic esters; medium complexity: hydroxycinnamic acids and phenylpropenes; and high complexity: quinones, flavonols and flavones). Phenols of low and medium complexity were the most abundant in all morphotypes, while those of high complexity, probably the most costly for plants, were nearly exclusive of some tall evergreen shrubs. In general, PG, MES and TES had low, intermediate and high phenol concentration (8.5, 27.2, 202.5 mg g−1DW, respectively) and richness (15, 25, 37 compounds, respectively) in leaves. The richness of phenols was significantly and positively related to phenol concentration. However, we did not find distinctive phenol compound patterns among morphotypes. Our results suggest that drought and, to some extent, herbivory have exerted selective selection pressure on richness and phenol concentration in leaves of contrasting morphotypes but the type of phenols accumulated probably depends on intrinsic species attributes within each morphotype.