Rate Of Ester Hydrolysis Research Articles

3AcFNP-59 for Positron Emission Tomography Imaging of Cholesterol Trafficking and Utilization.

Cholesteryl ester analogues of [18F]FNP-59 have the ability to provide information on cholesterol trafficking and utilization at earlier time points than those of [18F]FNP-59 or [131I]NP-59. It is well-known that free cholesterol and cholesteryl esters have differing distribution profiles and that they can be interconverted enzymatically. Substitution of the ester influences the rate of cholesterol ester hydrolysis and the subsequent mixing of cholesterol esters with the lipid pool in the body. This can be utilized by preparing esters that are more readily taken up by lipoprotein, are quickly hydrolyzed and mixed with the endogenous lipid pool and delivered to tissues of interest more quickly than free cholesterol analogues that require esterification for lipoprotein association. The acetyl ester of FNP-59 demonstrated the preferred uptake properties and response to adrenal cortical manipulation, indicating its ability to image hormone production. Finally, dosimetry studies were conducted in preparation for the clinical translation of [18F]3AcFNP-59.

Rapid paper-based optical sensing of Spilosoma obliqua nucleopolyhedrovirus via ester hydrolysis.

We have developed an easily scalable chromogenic probe for the dual-mode sensing of Spilosoma obliqua Nuclear polyhedrosis viruses (SpobNPV) in aqueous media. The mechanistic investigations establish that the imidazole-mediated hydrolysis of acyl ester linkage in which water (general base) acts as a nucleophile induces a pronounced change in the emission colour from blue to cyan. To the best of our knowledge, this is the first attempt at quantifying OBs of SpobNPV using a small molecule-based optical probe with a detection limit of 2.305 × 103 OBs mL-1. The rate of ester hydrolysis was dependent on both substrate and OBs concentration. Due to the naked eye response, paper strips were also developed for the rapid and onsite detection of SpobNPV. The operation procedure is straightforward and does not involve additional sample preparation steps. This makes the present protocol suitable for daily use. Interestingly, the present protocol is also quite efficient in estimating SpobNPV, even in several agricultural crop samples (for at least 15 crops). Such findings will add a new dimension to better managing Spilosoma obliqua and minimizing the extent of crop loss.

Ester Bond: Chemically Labile Yet Mechanically Stable.

Due to the dynamic nature of ester linkages, ester-bond-containing materials are well known for their outstanding degradability and stimuli responsiveness. However, whether ester hydrolysis is affected by mechanical forces remains unclear. Here, we develop a single-molecule assay to quantitatively study the force-dependent ester hydrolysis using an engineered circular permutant protein with a caged ester bond as a model. Our single-molecule force spectroscopy results show that the ester hydrolysis rate is surprisingly insensitive to forces, with a ∼7 s-1 dissociation rate that remains almost unchanged in the force range of 80 to 200 pN. Quantum calculations reveal that the ester hydrolysis involves an intermediate state formed by either H3O+- or OH--bonded tetrahedral intermediates. The measured ester-hydrolysis kinetics at the single-molecule level may primarily correspond to the rupture of these intermediate states. However, the rate-limiting step appears to be the formation of the tetrahedral intermediates, which cannot be quantitatively characterized in our experiments. Nonetheless, based on the quantum calculations, this step is also insensitive to applied forces. Altogether, our study suggests that the ester bond is chemically labile yet mechanically stable, serving as the basis for the design of responsive materials using ester bonds as mechanically inert units.

A multiple linear regression approach to the estimation of carboxylic acid ester and lactone alkaline hydrolysis rate constants

ABSTRACT Pesticides, pharmaceuticals, and other organic contaminants often undergo hydrolysis when released into the environment; therefore, measured or estimated hydrolysis rates are needed to assess their environmental persistence. An intuitive multiple linear regression (MLR) approach was used to develop robust QSARs for predicting base-catalyzed rate constants of carboxylic acid esters (CAEs) and lactones. We explored various combinations of independent descriptors, resulting in four primary models (two for lactones and two for CAEs), with a total of 15 and 11 parameters included in the CAE and lactone QSAR models, respectively. The most significant descriptors include pK a, electronegativity, charge density, and steric parameters. Model performance is assessed using Drug Theoretics and Cheminformatics Laboratory’s DTC-QSAR tool, demonstrating high accuracy for both internal validation (r 2 = 0.93 and RMSE = 0.41–0.43 for CAEs; r 2 = 0.90–0.93 and RMSE = 0.38–0.46 for lactones) and external validation (r 2 = 0.93 and RMSE = 0.43–0.45 for CAEs; r 2 = 0.94–0.98 and RMSE = 0.33–0.41 for lactones). The developed models require only low-cost computational resources and have substantially improved performance compared to existing hydrolysis rate prediction models (HYDROWIN and SPARC).

Zr(IV) Catalyst for the Ring-Opening Copolymerization of Anhydrides (A) with Epoxides (B), Oxetane (B), and Tetrahydrofurans (C) to Make ABB- and/or ABC-Poly(ester-alt-ethers).

Poly(ester-alt-ethers) can combine beneficial ether linkage flexibility and polarity with ester linkage hydrolysability, furnishing fully degradable polymers. Despite their promising properties, this class of polymers remains underexplored, in part due to difficulties in polymer synthesis. Here, a catalyzed copolymerization using commercially available monomers, butylene oxide (BO)/oxetane (OX), tetrahydrofuran (THF), and phthalic anhydride (PA), accesses a series of well-defined poly(ester-alt-ethers). A Zr(IV) catalyst is reported that yields polymer repeat units comprising a ring-opened PA (A), followed by two ring-opened cyclic ethers (B/C) (−ABB– or −ABC−). It operates with high polymerization control, good rate, and successfully enchains epoxides, oxetane, and/or tetrahydrofurans, providing a straightforward means to moderate the distance between ester linkages. Kinetic analysis of PA/BO copolymerization, with/without THF, reveals an overall second-order rate law: first order in both catalyst and butylene oxide concentrations but zero order in phthalic anhydride and, where it is present, zero order in THF. Poly(ester-alt-ethers) have lower glass-transition temperatures (−16 °C < Tg < 12 °C) than the analogous alternating polyesters, consistent with the greater backbone flexibility. They also show faster ester hydrolysis rates compared with the analogous AB polymers. The Zr(IV) catalyst furnishes poly(ester-alt-ethers) from a range of commercially available epoxides and anhydride; it presents a straightforward method to moderate degradable polymers’ properties.

Poly(2-ethyl-2-oxazoline) Conjugates with Salicylic Acid via Degradable Modular Ester Linkages.

Conjugation of drugs to polymers is a widely used approach to gain control over the release of therapeutics. In this contribution, salicylic acid, a multipurpose model drug, is conjugated to the biocompatible poly(2-ethyl-2-oxazoline) (PEtOx). The drug is attached to the side chains of a polymer carrier through a hydrolytically cleavable ester linker, via a sequential postpolymerization modification. The chemical modulation of this ester, i.e., by primary or secondary alcohols, is demonstrated to greatly influence the ester hydrolysis rate. This crucial parameter allows us to tune the in vitro kinetics of the sustained drug release for periods exceeding a month in phosphate-buffered saline (PBS). The synthetic accessibility of the cleavable linker, together with the modularity of the drug release rate offered by this approach, highlights the utility of this class of polymers in the field of long-lasting drug delivery systems for persistent and chronic disease treatment.

Insights into the Chemical Discovery of Remifentanil.

Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-acting Opioid Analgetics. By Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. J Med Chem 1991; 34:2202-8. Copyright 1991 American Chemical Society. Reprinted with permission.In an effort to discover a potent ultrashort-acting µ-opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent µ-opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[1-oxopropyl)phenylamino]-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for µ-opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent µ agonists in vitro, but depending upon the alkyl ester substitution, the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The [structure-activity relationships] with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

Peptide–Gold Nanoparticle Conjugates as Artificial Carbonic Anhydrase Mimics

We herein describe the design and synthesis of a catalytically active peptide–gold nanoparticle conjugate (Pep-Au-NP) that binds Zn(II) within its peptide monolayer and develops carbonic anhydrase activity. Specifically, a modified variant of the β-sheet forming IHIHIQI-peptide (IHQ), which forms an interstrand 3-His Zn(II)-binding site, was used as a ligand for spherical gold nanoparticles (Au-NPs). The resulting immobilized peptide maintains its ability to form β-sheets, as determined by circular dichroism (CD)-spectroscopy and, thus, maintains its ability to form Zn(II)-binding sites. The addition of Zn(II)-ions to the peptide–gold nanoparticle conjugates (Au@IHQ-NP) resulted in significant improvements in rates of ester hydrolysis of 4-nitrophenyl acetate (4-NPA) and the hydration of CO2 compared to the unconjugated peptide variants. Recycling of the catalyst revealed that Au@IHQ-NP remains intact with at least 94% of its initial activity after five rounds of CO2 hydration. The herein reported results reveal that Pep-Au-NPs are able to perform reactions catalyzed by natural metalloenzymes and open up new possibilities for the implementation of these conjugates.

Local environment-dependent kinetics of ester hydrolysis revealed by direct 1H NMR measurement of degrading hydrogels

We have demonstrated the use of a simple 1H NMR spectrometry-based method to directly measure the pseudo first-order hydrolytic cleavage rate constant (kobs) of methacrylate-derived ester crosslinkers in hydrogels composed of PEG, dextran, carboxymethyl dextran (CM-dextran) and hyaluronic acid (HA). Using this technique, we systematically examined how the local environment in the hydrogel influenced the rate of ester hydrolysis. Within the formulations being studied, the esters in the crosslinked polymer network (gel state) degraded 1.8 times faster than esters of similar chemistry in soluble polymers (solution state). Furthermore, the value of kobs was independent of the polymer concentration or the hydrogel network structure, although these parameters affected the swelling profiles in response to the hydrolytic degradation. On the other hand, the presence of the negatively charged carboxylate groups in the polymer chains decreased kobs in gel state, while only minimally affecting kobs in solution state. Hydrogels composed of negatively charged polymers (HA and CM-dextran) had a kobs about 30% smaller than hydrogels composed of neutral polymers (dextran and PEG). The reported method provides a reliable tool to resolve conflicting views about hydrogel degradation, and to guide the rational design of degradable hydrogel. Statement of significanceDegradable hydrogels are widely used in biological applications. A common degradation mechanism of the crosslinked polymer is by hydrolytic cleavage. However, the hydrogel micro-milieu do affect the behavior of the hydrolysable bonds, for example esters. There have been several conflicting speculations on how hydrogel composition would affect the macroscopic degradation behavior. In this report, we simply, but innovatively applied ordinary 1H NMR spectrometry-based method to probe the rate of ester cleavage in the native hydrogel milieu. We tried to answer whether these parameters will have direct influence on ester cleavage, or have indirect effect on the overall network disintegration behavior. This study provides quantitative evidences to assist theoretical modeling and to guide rational formulation design.

Tuning the Catalytic Activity and Substrate Specificity of Peptide‐Nanoparticle Conjugates

AbstractThe immobilization of cysteine‐containing peptides onto the surface of gold nanoparticles (Pep‐Au‐MPCs) emerged as a promising strategy towards the development of artificial enzymes. In this context we studied the effect the location of the catalytic unit within the peptide‐monolayer relative to the nanoparticle surface has on the esterolytic activity and substrate specificity of three Pep‐Au‐MPCs, that only differ in the position of the catalytic unit (surface proximal, intermediate, surface distal). Rates of ester hydrolysis were found to correlate with the hydrophobicity of the substrate and the position of the catalytic unit. Highly hydrophobic ester substrates are cleaved more efficiently surface proximal, whereas less hydrophobic substrates showed higher rates of hydrolysis in the intermediate region of the monolayer. Our studies reveal the importance the position of the catalytic center has on the catalytic activity and substrate specificity of peptide‐nanoparticle conjugates.

Charge-Shifting Polycations with Tunable Rates of Hydrolysis: Effect of Backbone Substituents on Poly[2-(dimethylamino)ethyl acrylates

While polycations based on 2-(dimethylamino)ethyl methacrylate and 2-(dimethylamino)ethyl acrylate are used in applications ranging from biomaterials to wastewater treatment, few studies have considered the remarkable differences in the hydrolytic stabilities of the respective ester groups. Here, we describe how the nature of nonmethyl α-substituents affect the rates of ester hydrolysis of such polymers, with an emphasis on the resulting shift of net polymer charge from cationic toward anionic. We introduce 2-(dimethylamino)ethyl 2-hydroxymethyl acrylate (DHMA) as a new, very hydrolytically labile, cationic monomer that can be used to form homopolymers as well as a means to tune copolymer hydrolysis. DHMA synthesis and free radical polymerization are described, including reactivity ratios for hydroxyl-protected derivatives of DHMA and 2-(dimethylamino)ethyl acrylate (DMAEA). Hydrolyses of PDHMA, P[DHMA-co-DMAEA], PDMAEA, and PDMAEMA in pH 5 and 7 buffer are reported. The presence of the hydroxymethyl α-su...

Carboxylic acid ester hydrolysis rate constants for food and beverage aroma compounds

AbstractAroma compounds in the Flavornet database were screened for potentially hydrolysable carboxylic acid ester functionalities. Of 738 aroma compounds listed in this database, 140 molecules contain carboxylic acid ester groups that may be amenable to hydrolysis in various food and beverage products. Acid‐ (kA) and base‐ (kB) catalysed and neutral (kN) hydrolysis rate constants in pure water at 25°C were calculated for these aroma compounds. Where available, good agreement between theoretical and experimental hydrolytic half‐lives was obtained at various pH values. Wide ranges and broad frequency distributions for kA, kB, and kN are expected among the various hydrolyzable aroma compounds, with calculated kA ranging from 3.7 × 10‐8 to 4.7 × 10‐4 M‐1 s‐1, calculated kB ranging from 4.3 × 10‐4 to 43 M‐1 s‐1, and calculated kN ranging from 4.2 × 10‐17 to 7.6 × 10‐9 M‐1 s‐1. The resulting hydrolytic half‐lives also range widely, from 10 days to 370 years at pH 2.8, 18 days to 4,900 years at pH 4.0, 1.8 days to 470 years at pH 7.0, and 26 minutes to 5.1 years at pH 9.0. The findings illustrate the importance of considering abiotic hydrolysis and matrix pH when modelling the evolution of sensory characteristics for foods and beverages with carboxylic acid ester based aroma compounds. Copyright © 2016 John Wiley &amp; Sons, Ltd.

Polymeric Nanogels with Tailorable Degradation Behavior.

The aim of this study is to design a polymeric nanogel system with tailorable degradation behavior. To this end, hydroxyethyl methacrylate-oligoglycolates-derivatized poly(hydroxypropyl methacrylamide) (pHPMAm-Gly-HEMA) and hydroxyethyl methacrylamide-oligoglycolates-derivatized poly(hydroxyethyl methacrylamide) (pHEMAm-Gly-HEMAm) are synthesized and characterized. pHEMAm-Gly-HEMAm shows faster hydrolysis rates of both carbonate and glycolate esters than the same ester groups of pHPMAm-Gly-HEMA. pHEMAm-Gly-HEMAm nanogels have tailorable degradation kinetics from 24 h to more than 4 d by varying their crosslink densities. It is shown that the release of a loaded macromolecular model drug is controlled by degradation of nanogels. The nanogels show similar cytocompatibility as PLGA nanoparticles and are therefore considered to be attractive systems for drug delivery.

Polymerized micelles based on poly-11-(acryloylamino)undecanoic acid: aggregation properties and influence on the hydrolysis rate of phosphorous acid esters

The sizes (hydrodynamic diameter) and ζ potentials of sodium N-acryloyl-11-aminoundecanoate and poly(sodium N-acryloyl-11-aminoundecanoate) with molecular weights of 10 000, 100 000, and 250 000 were determined using dynamic light scattering. The particle size of the formed aggregates of the macromolecules depends on the molecular weight. The value of ζ potential of the aggregates increases with an increase in the molecular weight of the polymer. The influence of the systems based on the monomer and polymers on the alkaline hydrolysis of 4-nitrophenyl chloroethyl methylphosphonate was studied by spectrophotometry. The character and extent of effect of the system depend on the molecular weight of the polymer and type of the counterion. The strongest inhibition of the process (by 65 times) is observed in the case of poly(sodium N-acryloyl-11-aminoundecanoate) with the molecular weight 100 000.

Enantioselective ester hydrolysis by an achiral catalyst co-embedded with chiral amphiphiles into a vesicle membrane

Co-embedding of an amphiphilic non-chiral hydrolysis catalyst with amphiphilic chiral additives into the membrane of a phospholipid vesicle induces different rates of ester hydrolysis for enantiomeric amino acid esters.

Surface plasmon resonance promotion of homogeneous catalysis using a gold nanoparticle platform

Reaction of 10 nm gold nanoparticles (AuNPs) with a thiol-functionalized bipyridine copper(II) complex, Cu[(N-(6-mercaptohexyl)-2,2′-bipyridinyl-5-carboxamide)]Cl2 (3), and (1-mercaptohex-6-yl)tri(ethylene glycol) (5) in different ratios resulted in mixed monolayer modified NPs with varying surface coverage of capping agent. The copper complex modified NPs were used for surface plasmon resonance (SPR) promoted homogeneous catalysis applied to the hydrolysis of the nerve agent methyl parathion (MeP) at pH 8.0. Low power green laser (532 nm) irradiation of solutions of modified AuNPs with MeP resulted in significant increase in the rate of phosphate ester hydrolysis which could not be attributed to a thermal process. Ratios of initial rates (laser/dark) at high substrate concentrations of MeP as a function of copper catalyst coverage were determined. A possible mechanism for catalytic enhancement involving dissociation of catalytically inactive hydroxy-bridged Cu(II) dimer is discussed.

Modeling biophysical and biological properties from the characteristics of the molecular electron density, electron localization and delocalization matrices, and the electrostatic potential.

The electron density and the electrostatic potential are fundamentally related to the molecular hamiltonian, and hence are the ultimate source of all properties in the ground- and excited-states. The advantages of using molecular descriptors derived from these fundamental scalar fields, both accessible from theory and from experiment, in the formulation of quantitative structure-to-activity and structure-to-property relationships, collectively abbreviated as QSAR, are discussed. A few such descriptors encode for a wide variety of properties including, for example, electronic transition energies, pKa's, rates of ester hydrolysis, NMR chemical shifts, DNA dimers binding energies, π-stacking energies, toxicological indices, cytotoxicities, hepatotoxicities, carcinogenicities, partial molar volumes, partition coefficients (log P), hydrogen bond donor capacities, enzyme–substrate complementarities, bioisosterism, and regularities in the genetic code. Electronic fingerprinting from the topological analysis of the electron density is shown to be comparable and possibly superior to Hammett constants and can be used in conjunction with traditional bulk and liposolubility descriptors to accurately predict biological activities. A new class of descriptors obtained from the quantum theory of atoms in molecules' (QTAIM) localization and delocalization indices and bond properties, cast in matrix format, is shown to quantify transferability and molecular similarity meaningfully. Properties such as “interacting quantum atoms (IQA)” energies which are expressible into an interaction matrix of two body terms (and diagonal one body “self” terms, as IQA energies) can be used in the same manner. The proposed QSAR-type studies based on similarity distances derived from such matrix representatives of molecular structure necessitate extensive investigation before their utility is unequivocally established. © 2014 The Author and the Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

FT-IR characterization and hydrolysis of PLA-PEG-PLA based copolyester hydrogels with short PLA segments and a cytocompatibility study

A series of the biodegradable copolyester hydrogels was prepared using a redox-initiated polymerization with a constant 1:9 mole ratio of the Boltorn-based acrylate and diacrylate triblock comacromonomers. The Boltorn (R) macromonomer was derived from the hyperbranched polyester Boltorn H20, which was functionalized at each terminus with poly(ethylene glycol) acrylate, and the diacrylate triblock macromonomer was poly (lactide-b-ethylene glycol-b-lactide) diacrylate. The hydrolysis of the copolyesters at pH 7.4 in a phosphate buffered saline solution at 37 degrees C was studied using ATR-FTIR spectroscopy. It was found that the presence of the Boltorn, the PEG, and lactide block lengths both play vital roles in determining the structure-property relationships in these materials. The ATR-FTIR studies showed that with increasing lactide segment length, the rate of ester hydrolysis increased due to the increased concentration of the hydrolytically sensitive poly(lactic acid) (PLA) ester groups in the network. However, incorporation of Boltorn into the PLA-PEG-PLA copolymer did not significantly change the kinetic rate constant for hydrolysis of the PLA segments. The cytocompatibility of a typical one of these materials in the presence of its degradation by-products was assessed using cultured osteoblasts from the rat. The hydrogel was degraded for 28 days and found to be cytocompatible with osteoblasts over days 23 to 28 of the hydrolysis period. (c) 2013 Wiley Periodicals, Inc.

Oxidation-Accelerated Hydrolysis of the Ortho Ester-Containing Acid-Labile Polymers.

We report a versatile method to tune the hydrolysis of the ortho ester-containing block copolymers by covalently incorporating oxidation-sensitive phenylboronic ester units. A series of block copolymers which contain a polyethylene glycol (PEG) block and a hydrophobic segment composed of different amounts of pendent ortho ester and phenylboronic ester groups were synthesized. These copolymers can self-assemble into narrowly dispersed micelle-like nanoparticles in phosphate buffer. The kinetics of phenylboronic ester oxidation and ortho ester hydrolysis in the nanoparticles were studied at different pH and H2O2 concentration. The results indicated that the phenylboronic ester oxidation rate was faster than the ortho ester hydrolysis rate at neutral pH, and both processes were accelerated with increasing H2O2 concentration. Nanoparticles which are extremely sensitive to the biorelevant concentration of H2O2 (50 μM) at pH 7.4 were obtained, suggesting great promise for inflammation-specific drug delivery.

A category approach to predicting the repeated-dose hepatotoxicity of allyl esters

We tested a category approach to predict the hepatotoxic effects of repeated doses of allyl esters using a new database for repeated-dose toxicity. Based on information on hepatotoxic mechanism of allyl acetate, the category was defined as allyl esters that are hydrolyzed to allyl alcohol. Allyl alcohol is readily oxidized to acrolein in the liver, causing hepatotoxicity. Seventeen marketed allyl esters were obtained and grouped into category by identifying or predicting allyl alcohol formation. Allyl esters with a saturated straight alkyl carboxylic acid moiety (allyl acetate, hexanoate and heptanoate as tested species, and allyl butyrate, pentanoate, octanoate, nonanoate and decanoate as untested species) are likely similar in rate of ester hydrolysis, thereby defining subcategory 1. NOAEL and LOAEL for the hepatotoxic effects were estimated at 0.12 and 0.25mmol/kg/d for the untested species, based on those of allyl acetate. The remaining nine allyl esters with other alkyl or aromatic carboxylic acid moieties were placed in subcategory 2: their hepatotoxicity levels were not predictable due to an unclear match between their degree of structural complexity and rate of hydrolysis. Our results demonstrate the usefulness of the category approach for predicting the hepatotoxicity of untested allyl esters with saturated straight alkyl chains.