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Esterases and lipases can process amphiphilic esters used as drugs and prodrugs and impact their pharmacokinetics and biodistribution. These hydrolases can also process ester components of drug delivery systems (DDSs), thus triggering DDSs destabilization with premature cargo release. In this study we tested and optimized assays that allowed us to quantify and compare individual esterase contributions to the degradation of substrates of increased lipophilicity and to establish limitations in terms of substrates that can be processed by a specific esterase/lipase. We have studied the impact of carbonic anhydrase; phospholipases A1, A2, C and D; lipoprotein lipase; and standard lipase on the hydrolysis of 4-nitrophenyl acetate, 4-nitrophenyl palmitate, DGGR and POPC liposomes, drawing structure–property relationships. We found that the enzymatic activity of these proteins was highly dependent on the lipophilicity of the substrate used to assess them, as expected. The activity observed for classical esterases was diminished when lipophilicity of the substrate increased, while activity observed for lipases generally increased, following the interfacial activation model, and was highly dependent on the type of lipase and its structure. The assays developed allowed us to determine the most sensitive methods for quantifying enzymatic activity against substrates of particular types and lipophilicity.

In order to modify amino acids, the C-terminus carboxylic acid usually needs to be protected, typically as a methyl ester. However, standard cleavage of methyl esters requires either highly basic or acidic conditions, which are not compatible with Fmoc or acid-labile protecting groups. This highlights the need for orthogonal conditions that permit selective deprotection of esters to create SPPS-ready amino acids. Herein, mild orthogonal ester hydrolysis conditions are systematically explored using calcium(II) iodide as a protective agent for the Fmoc protecting group and optimized for a broad scope of amino esters. Our optimized reaction improved on the already known trimethyltin hydroxide, as it produced better yields with greener, inexpensive chemicals and a less extensive energy expenditure.

One of the current and serious environmental problems is the pollution due to microplastics. There is an urgent need for biodegradable and bio-based materials for numerous applications, including food packaging. In this work we examine the bio-based polyester cutin for its potential to be used as food packaging material, in terms of migration, based on the Hansen Solubility Parameters (HSP). Cutin is a cross-linked polymer that is swelled by various solvents. We use the degree of swelling of cutin in carefully selected solvents of various polarities in order to estimate the HSP of cutin. Some solvents can induce alteration of the chemical structure of cutin, as proven by Fourier Transform Infrared (FTIR) measurements. This interferes with the process of estimation of the HSP and is discussed in depth. The distance Ra and the Relative Energy Difference (RED) between the HSP of cutin and various food components are calculated and used to predict the existence of favorable interactions between cutin and the food components, which is translated to a high probability for the existence of migration and permeation. Experimental confirmation of one prediction based on HSP is provided by UV-VIS photometry. Similar calculations were performed for other polyesters (poly(lactic acid) and poly(hydroxy butyrate)). Cutin exhibits compatibility with substances of low polarity, such as fats and lipids and non-polar compounds found in essential oils. Thus, migration into fatty foods is expected as well as sorption and permeation of some (volatile) compounds into cutin. Nevertheless, we conclude that the overall migration risk for cutin is lower than the one of other bio-based polyesters. HSP can be used for initial screening of potential migration risks; however, further research is necessary in order to assess the occurrence, extent, and significance of the actual migration.

Iridoids are widely found from species of Bignoniaceae family and exhibit several biological activities, such as anti-inflammatory, antimicrobial, antioxidant, and antitumor. Specioside is an iridoid found from Tabebuia species, mainly in Tabebuia aurea. Thus, here fungus-mediated biotransformation of the iridoid specioside was investigated by seven fungi. The fungus-mediated biotransformation reactions resulted in a total of nineteen different analogs by fungus Aspergillus niger, Aspergillus flavus, Aspergillus japonicus, Aspergillus terreus, Aspergillus niveus, Penicillium crustosum, and Thermoascus aurantiacus. Non-glycosylated specioside was the main metabolite observed. The other analogs were yielded from ester hydrolysis, hydroxylation, methylation, and hydrogenation reactions. The non-glycosylated specioside and coumaric acid were yielded by all fungi-mediated biotransformation. Thus, fungus applied in this study showed the ability to perform hydroxylation and glycosidic, as well as ester hydrolysis reactions from glycosylated iridoid.Key points• The biotransformation of specioside by seven fungi yielded nineteen analogs.• The non-glycosylated specioside was the main analog obtained.• Ester hydrolysis, hydroxylation, methylation, and hydrogenation reactions were observe

5F-MDMB-PINACA and 4F-MDMB-BINACA are synthetic cannabinoids (SCs) that elicit cannabinoid psychoactive effects. Defining pharmacokinetic–pharmacodynamic (PK–PD) relationships governing SCs and their metabolites are paramount to investigating their in vivo toxicological outcomes. However, the disposition kinetics and cannabinoid receptor (CB) activities of the primary metabolites of SCs are largely unknown. Additionally, reasons underlying the selection of ester hydrolysis metabolites (EHMs) as urinary biomarkers are often unclear. Here, metabolic reaction phenotyping was performed to identify key metabolizing enzymes of the parent SCs. Hepatic clearances of parent SCs and their EHMs were estimated from microsomal metabolic stability studies. Renal clearances were simulated using a mechanistic kidney model incorporating in vitro permeability and organic anionic transporter 3 (OAT3)-mediated uptake data. Overall clearances were considered in tandem with estimated volumes of distribution for in vivo biological half-lives (t1/2) predictions. Interactions of the compounds with CB1 and CB2 were investigated using a G-protein coupled receptor activation assay. We demonstrated that similar enzymatic isoforms were implicated in the metabolism of 5F-MDMB-PINACA and 4F-MDMB-BINACA. Our in vivo t1/2 determinations verified the rapid elimination of parent SCs and suggest prolonged circulation of their EHMs. The pronounced attenuation of the potencies and efficacies of the metabolites against CB1 and CB2 further suggests how toxic manifestations of SC abuse are likely precipitated by augmented exposure to parent SCs. Notably, basolateral OAT3-mediated uptake of the EHMs substantiates their higher urinary abundance. These novel insights underscore the importance of mechanistic, quantitative and systematic characterization of PK–PD relationships in rationalizing the toxicities of SCs.

O-GlcNAcylation is an essential post-translational modification that occurs on nuclear and cytoplasmic proteins, regulating their function in response to cellular stress and altered nutrient availability. O-GlcNAc transferase (OGT) is the enzyme that catalyzes this reaction and represents a potential therapeutic target, whose biological role is still not fully understood. To support this research field, a series of cell-permeable, low-nanomolar OGT inhibitors were recently reported. In this study, we resynthesized the most potent OGT inhibitor of the library, OSMI-4, and we used it to investigate OGT inhibition in different human cell lines. The compound features an ethyl ester moiety that is supposed to be cleaved by carboxylesterases to generate its active metabolite. Our LC-HRMS analysis of the cell lysates shows that this is not always the case and that, even in the cell lines where hydrolysis does not occur, OGT activity is inhibited.

•5F-ADB is regarded as one of the most dangerous synthetic cannabinoids.•5F-ADB is currently the most frequently consumed SC in Turkey.•Seventy 5F-ADB intoxication case reports are presented.•5F-ADB and its metabolite are detected and quantified in blood and urine.•Bucket method is used for inhalation in Turkey. 5F-ADB (methyl 2-{[1-(5-fluoropentyl)-1H-indazole-3-carbonyl]amino}-3,3-dimethylbutanoate) is a frequently abused new synthetic cannabinoid that has been sold since at least the end of 2014 on the drug market. It has been classified as an illicit drug in most European countries, and also in Turkey, Japan, and the United States. In this study, 5F-ADB and its methyl ester metabolite were determined in the blood and urine samples taken from fatal cases using liquid chromatography–highresolution mass spectrometry (LC–HRMS). The extraction of samples was performed using a solid-phase extraction method, followed by LC–HRMS analysis. The method was fully validated for linearities, limits of detection (LODs), limits of quantification (LOQs), recoveries, matrix effects, process efficiencies, accuracies, precisions, and stabilities and was applied to 70 blood and 36 urine samples from fatal cases where 5F-ADB was the only drug detected. The LODs were between 0.08 and 0.10ng/mL, and LOQs were between 0.10 and 0.12ng/mL for both blood and urine samples. 5F-ADB and its methyl ester hydrolysis metabolite were found at the blood concentrations ranging from 0.10 to 1.55ng/mL (mean=0.40ng/mL) and 0.15 to 23.4ng/mL (mean=2.69ng/mL), respectively. 5F-ADB was not detected in any urine samples. 5F-ADBmethyl ester hydrolysis metabolite was detected in 35 urine samples with a detection range of 0.28–72.2ng/mL and a mean of 9.02ng/mL. The synthetic cannabinoid 5F-ADB and its methyl ester metabolite were identified and quantified in authentic human blood and/or urine specimens obtained from 70 fatal cases. The method was successfully applied to postmortem blood and urine samples.

Background/Objectives: Levocetirizine (LCZ) is a second-generation antihistamine with minimal central nervous system effects. However, its short half-life necessitates daily dosing, potentially reducing adherence in pediatric populations. This study aimed to develop a long-acting injectable LCZ formulation by synthesizing lipophilic prodrugs and evaluating their physicochemical stability, enzymatic hydrolysis, and pharmacokinetics in vivo. Methods: Two prodrugs of LCZ, LCZ decanoate (LCZ-D) and LCZ laurate (LCZ-L), were synthesized via esterification with alkyl alcohols. The compounds were characterized using NMR, FT-IR, and DSC. Prodrugs were formulated with an oil-based vehicle (castor oil and benzyl benozate), and their hydrolysis was evaluated using porcine liver esterase (PLE) and rat plasma. Pharmacokinetic profiles were assessed in Sprague Dawley rats after oral or intramuscular administration. Stability was tested at 25 °C, 40 °C, and 60 °C for 6 weeks. Results: LCZ-D and LCZ-L exhibited first-order hydrolysis kinetics, with rates following the order of PLE (2.0 > 0.5 units/mL) > plasma > PLE (0.2 units/mL). The Cmax of LCZ-D and LCZ-L were 13.95 and 5.12 ng/mL, respectively, with corresponding AUC0–45d values of 6423.12 and 2109.22 h·ng/mL. Formulations containing excipients with lower log P values led to increased systemic exposure. All formulations maintained therapeutic plasma concentrations for over 30 days. The inclusion of the antioxidant BHT (0.03% v/v) improved oxidative stability, reducing degradation at 60 °C from 4.72% to 1.17%. Conclusions: All formulations demonstrated potential for the long-acting delivery of LCZ, maintaining therapeutic plasma levels for over 30 days. Moreover, the release behavior and systemic exposure could be effectively modulated by excipient selection.

Solid materials such as alumina-silicate microspheres (ASMS), manganese dioxide, starch derived carbon (SDC), alumina, graphite carbon (GC) and coke were used as catalysts for the alkaline hydrolysis of benzyl benzoate using aqueous sodium hydroxide. The benzoic acid yield as a function of time, ester (0.5–2.5 M) and sodium hydroxide (0.4–2.4 M) concentration, temperature (318–358 K) and catalyst dose (0.1–0.5 g) was determined. Among the six, three of the catalysts were mainly chosen based on their catalytic efficiency on the hydrolysis of benzyl benzoate ester. The real purpose of this work was in the interest of identifying cheap solid catalysts with appreciable hydrolysis efficiency. The kinetic and thermodynamic methods in accordance with the experimental variables were employed. The reuse potential, analysis of catalyst’s cost and the characterization studies for the catalysts were carried out and detailed in the present research paper.

All reactions are accelerated by an increase in temperature, but the magnitude of that effect on very slow reactions does not seem to have been fully appreciated. The hydrolysis of polysaccharides, for example, is accelerated 190,000-fold when the temperature is raised from 25 to 100 °C, while the rate of hydrolysis of phosphate monoester dianions increases 10,300,000-fold. Moreover, the slowest reactions tend to be the most heat-sensitive. These tendencies collapse, by as many as five orders of magnitude, the time that would have been required for early chemical evolution in a warm environment. We propose, further, that if the catalytic effect of a \"proto-enzyme\"—like that of modern enzymes—were mainly enthalpic, then the resulting rate enhancement would have increased automatically as the environment became cooler. Several powerful nonenzymatic catalysts of very slow biological reactions, notably pyridoxal phosphate and the ceric ion, are shown to meet that criterion. Taken together, these findings greatly reduce the time that would have been required for early chemical evolution, countering the view that not enough time has passed for life to have evolved to its present level of complexity.