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Claus Larsen - One of the best experts on this subject based on the ideXlab platform.
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bioreversible derivatives of phenol 2 reactivity of Carbonate Esters with fatty acid like structures towards hydrolysis in aqueous solutions
Molecules, 2007Co-Authors: Jesper Ostergaard, Claus LarsenAbstract:Abstract: A series of model phenol Carbonate ester prodrugs encompassing derivatives with fatty acid-like structures were synthesized and their stability as a function of pH (range 0.4 – 12.5) at 37 o C in aqueous buffer solutions investigated. The hydrolysis rates in aqueous solutions differed widely, depending on the selected pro-moieties (alkyl and aryl substituents). The observed reactivity differences could be rationalized by the inductive and steric properties of the substituent groups when taking into account that the mechanism of hydrolysis may change when the type of pro-moiety is altered, e.g. n -alkyl vs. -butyl. tHydrolysis of the phenolic carbonatbonyloxy)-acetic acide ester 2-(phenoxycar was increased due to intramolecular catalysis, as compared to the derivatives synthesized from ω-hydroxy carboxylic acids with longer alkyl chains. The Carbonate Esters appear to be less reactive towards specific acid and base catalyzed hydrolysis than phenyl acetate. The results underline that it is unrealistic to expect that phenolic Carbonate ester prodrugs can be utilized in ready to use aqueous formulations. The stability of the Carbonate ester derivatives with fatty acid-like structures, expected to interact with the plasma protein human serum albumin, proved sufficient for further
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bioreversible derivatives of phenol 1 the role of human serum albumin as related to the stability and binding properties of Carbonate Esters with fatty acid like structures in aqueous solution and biological media
Molecules, 2007Co-Authors: Jesper Ostergaard, Claus LarsenAbstract:With the overall objective of assessing the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving the pharmacokinetics of drug substances, a series of model Carbonate ester prodrugs of phenol, encompassing derivatives with fatty acid-like structures, were characterized in vitro. Stability of the derivatives was studied in aqueous solution, human serum albumin solution, human plasma, and rat liver homogenate at 37°C. Stability of the derivatives in aqueous solution varied widely, with half-lives ranging from 31 to 1.7 × 104 min at pH 7.4 and 37°C. The Carbonate Esters were subject to catalysis by plasma esterases except for the t-butyl and acetic acid derivatives, which were stabilized in both human plasma and human serum albumin solutions relative to buffer. In most cases, however, hydrolysis was accelerated in the presence of human serum albumin indicating that the derivatives interacted with the protein, a finding which was confirmed using the p-nitrophenyl acetate kinetic assay. Different human serum albumin binding properties of the phenol model prodrugs with fatty acid-like structure and neutral Carbonate Esters were observed. In the context of utilizing plasma protein binding in combination with the prodrug approach for optimizing drug pharmacokinetics, the esterase-like properties of human serum albumin towards the Carbonate Esters potentially allowing the protein to act as a catalyst of parent compound regenerations is interesting.
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Bioreversible derivatives of phenol. 2. Reactivity of Carbonate Esters with fatty acid-like structures towards hydrolysis in aqueous solutions.
Molecules, 2007Co-Authors: Jesper Ostergaard, Claus LarsenAbstract:A series of model phenol Carbonate ester prodrugs encompassing derivatives with fatty acid-like structures were synthesized and their stability as a function of pH (range 0.4 – 12.5) at 37°C in aqueous buffer solutions investigated. The hydrolysis rates in aqueous solutions differed widely, depending on the selected pro-moieties (alkyl and aryl substituents). The observed reactivity differences could be rationalized by the inductive and steric properties of the substituent groups when taking into account that the mechanism of hydrolysis may change when the type of pro-moiety is altered, e.g. n-alkyl vs. t-butyl. Hydrolysis of the phenolic Carbonate ester 2-(phenoxycarbonyloxy)-acetic acid was increased due to intramolecular catalysis, as compared to the derivatives synthesized from ω-hydroxy carboxylic acids with longer alkyl chains. The Carbonate Esters appear to be less reactive towards specific acid and base catalyzed hydrolysis than phenyl acetate. The results underline that it is unrealistic to expect that phenolic Carbonate ester prodrugs can be utilized in ready to use aqueous formulations. The stability of the Carbonate ester derivatives with fatty acid-like structures, expected to interact with the plasma protein human serum albumin, proved sufficient for further in vitro and in vivo evaluation of the potential of utilizing HSA binding in combination with the prodrug approach for optimization of drug pharmacokinetics.
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Bioreversible Derivatives of Phenol. 1. The Role of Human Serum Albumin as Related to the Stability and Binding Properties of Carbonate Esters with Fatty Acid-like Structures in Aqueous Solution and Biological Media
Molecules, 2007Co-Authors: Jesper Ostergaard, Claus LarsenAbstract:Abstract: With the overall objective of assessing the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving the pharmacokinetics of drug substances, a series of model Carbonate ester prodrugs of phenol, encompassing derivatives with fatty acid-like structures, were characterized in vitro . Stability of the derivatives was studied in aqueous solution, human serum albumin solution, human plasma, and rat liver homogenate at 37 o C. Stability of the derivatives in aqueous solution varied widely, with half-lives ranging from 31 to 1.7 × 10 4 min at pH 7.4 and 37 o C. The Carbonate Esters were subject to catalysis by plasma esterases except for the t -butyl and acetic acid derivatives, which were stabilized in both human plasma and human serum albumin solutions relative to buffer. In most cases, however, hydrolysis was accelerated in the presence of human serum albumin indicating that the derivatives interacted with the protein, a finding which was confirmed using the
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determination of octanol water partition coefficients for Carbonate Esters and other small organic molecules by microemulsion electrokinetic chromatography
Electrophoresis, 2003Co-Authors: Jesper Ostergaard, Steen Honore Hansen, Claus Larsen, Christian Schou, Niels H H HeegaardAbstract:: Microemulsion electrokinetic chromatography (MEEKC) was assessed as a tool for determination of octanol-water partition coefficients using 34 solutes encompassing 8 Carbonate Esters. It was confirmed that microemulsions containing 1.44-2.88% w/w SDS, 6.49% w/w 1-butanol, and 0.82% w/w n-heptane constitute a good model of octanol-water partitioning in the pH range of 1.4-7.4. Use of the migration index concept led to improved repeatability of the MEEKC method compared to the use of retention factors. Using a dynamical coating, a high electroosmotic flow at pH 1.4 and 4.75 was achieved expanding the practical pH working range of the MEEKC system. The correlation obtained between the migration index and log P was unaffected by pH indicating that the properties of the microemulsion droplets and, thus, partitioning are independent of pH. No evidence for congeneric behavior was found for the sample set comprising solutes with different hydrogen bonding properties suggesting that simple reference compounds can be used as calibrators. Lipophilicity estimates for the series of Carbonate Esters were obtained. The increase in lipophilicity with chain length was smaller than expected from the Hansch substituent constant, pi.
Jesper Ostergaard - One of the best experts on this subject based on the ideXlab platform.
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bioreversible derivatives of phenol 2 reactivity of Carbonate Esters with fatty acid like structures towards hydrolysis in aqueous solutions
Molecules, 2007Co-Authors: Jesper Ostergaard, Claus LarsenAbstract:Abstract: A series of model phenol Carbonate ester prodrugs encompassing derivatives with fatty acid-like structures were synthesized and their stability as a function of pH (range 0.4 – 12.5) at 37 o C in aqueous buffer solutions investigated. The hydrolysis rates in aqueous solutions differed widely, depending on the selected pro-moieties (alkyl and aryl substituents). The observed reactivity differences could be rationalized by the inductive and steric properties of the substituent groups when taking into account that the mechanism of hydrolysis may change when the type of pro-moiety is altered, e.g. n -alkyl vs. -butyl. tHydrolysis of the phenolic carbonatbonyloxy)-acetic acide ester 2-(phenoxycar was increased due to intramolecular catalysis, as compared to the derivatives synthesized from ω-hydroxy carboxylic acids with longer alkyl chains. The Carbonate Esters appear to be less reactive towards specific acid and base catalyzed hydrolysis than phenyl acetate. The results underline that it is unrealistic to expect that phenolic Carbonate ester prodrugs can be utilized in ready to use aqueous formulations. The stability of the Carbonate ester derivatives with fatty acid-like structures, expected to interact with the plasma protein human serum albumin, proved sufficient for further
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bioreversible derivatives of phenol 1 the role of human serum albumin as related to the stability and binding properties of Carbonate Esters with fatty acid like structures in aqueous solution and biological media
Molecules, 2007Co-Authors: Jesper Ostergaard, Claus LarsenAbstract:With the overall objective of assessing the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving the pharmacokinetics of drug substances, a series of model Carbonate ester prodrugs of phenol, encompassing derivatives with fatty acid-like structures, were characterized in vitro. Stability of the derivatives was studied in aqueous solution, human serum albumin solution, human plasma, and rat liver homogenate at 37°C. Stability of the derivatives in aqueous solution varied widely, with half-lives ranging from 31 to 1.7 × 104 min at pH 7.4 and 37°C. The Carbonate Esters were subject to catalysis by plasma esterases except for the t-butyl and acetic acid derivatives, which were stabilized in both human plasma and human serum albumin solutions relative to buffer. In most cases, however, hydrolysis was accelerated in the presence of human serum albumin indicating that the derivatives interacted with the protein, a finding which was confirmed using the p-nitrophenyl acetate kinetic assay. Different human serum albumin binding properties of the phenol model prodrugs with fatty acid-like structure and neutral Carbonate Esters were observed. In the context of utilizing plasma protein binding in combination with the prodrug approach for optimizing drug pharmacokinetics, the esterase-like properties of human serum albumin towards the Carbonate Esters potentially allowing the protein to act as a catalyst of parent compound regenerations is interesting.
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Bioreversible derivatives of phenol. 2. Reactivity of Carbonate Esters with fatty acid-like structures towards hydrolysis in aqueous solutions.
Molecules, 2007Co-Authors: Jesper Ostergaard, Claus LarsenAbstract:A series of model phenol Carbonate ester prodrugs encompassing derivatives with fatty acid-like structures were synthesized and their stability as a function of pH (range 0.4 – 12.5) at 37°C in aqueous buffer solutions investigated. The hydrolysis rates in aqueous solutions differed widely, depending on the selected pro-moieties (alkyl and aryl substituents). The observed reactivity differences could be rationalized by the inductive and steric properties of the substituent groups when taking into account that the mechanism of hydrolysis may change when the type of pro-moiety is altered, e.g. n-alkyl vs. t-butyl. Hydrolysis of the phenolic Carbonate ester 2-(phenoxycarbonyloxy)-acetic acid was increased due to intramolecular catalysis, as compared to the derivatives synthesized from ω-hydroxy carboxylic acids with longer alkyl chains. The Carbonate Esters appear to be less reactive towards specific acid and base catalyzed hydrolysis than phenyl acetate. The results underline that it is unrealistic to expect that phenolic Carbonate ester prodrugs can be utilized in ready to use aqueous formulations. The stability of the Carbonate ester derivatives with fatty acid-like structures, expected to interact with the plasma protein human serum albumin, proved sufficient for further in vitro and in vivo evaluation of the potential of utilizing HSA binding in combination with the prodrug approach for optimization of drug pharmacokinetics.
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Bioreversible Derivatives of Phenol. 1. The Role of Human Serum Albumin as Related to the Stability and Binding Properties of Carbonate Esters with Fatty Acid-like Structures in Aqueous Solution and Biological Media
Molecules, 2007Co-Authors: Jesper Ostergaard, Claus LarsenAbstract:Abstract: With the overall objective of assessing the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving the pharmacokinetics of drug substances, a series of model Carbonate ester prodrugs of phenol, encompassing derivatives with fatty acid-like structures, were characterized in vitro . Stability of the derivatives was studied in aqueous solution, human serum albumin solution, human plasma, and rat liver homogenate at 37 o C. Stability of the derivatives in aqueous solution varied widely, with half-lives ranging from 31 to 1.7 × 10 4 min at pH 7.4 and 37 o C. The Carbonate Esters were subject to catalysis by plasma esterases except for the t -butyl and acetic acid derivatives, which were stabilized in both human plasma and human serum albumin solutions relative to buffer. In most cases, however, hydrolysis was accelerated in the presence of human serum albumin indicating that the derivatives interacted with the protein, a finding which was confirmed using the
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determination of octanol water partition coefficients for Carbonate Esters and other small organic molecules by microemulsion electrokinetic chromatography
Electrophoresis, 2003Co-Authors: Jesper Ostergaard, Steen Honore Hansen, Claus Larsen, Christian Schou, Niels H H HeegaardAbstract:: Microemulsion electrokinetic chromatography (MEEKC) was assessed as a tool for determination of octanol-water partition coefficients using 34 solutes encompassing 8 Carbonate Esters. It was confirmed that microemulsions containing 1.44-2.88% w/w SDS, 6.49% w/w 1-butanol, and 0.82% w/w n-heptane constitute a good model of octanol-water partitioning in the pH range of 1.4-7.4. Use of the migration index concept led to improved repeatability of the MEEKC method compared to the use of retention factors. Using a dynamical coating, a high electroosmotic flow at pH 1.4 and 4.75 was achieved expanding the practical pH working range of the MEEKC system. The correlation obtained between the migration index and log P was unaffected by pH indicating that the properties of the microemulsion droplets and, thus, partitioning are independent of pH. No evidence for congeneric behavior was found for the sample set comprising solutes with different hydrogen bonding properties suggesting that simple reference compounds can be used as calibrators. Lipophilicity estimates for the series of Carbonate Esters were obtained. The increase in lipophilicity with chain length was smaller than expected from the Hansch substituent constant, pi.
Somsak Ruchirawat - One of the best experts on this subject based on the ideXlab platform.
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synthesis of aryl α keto Esters via the rearrangement of aryl cyanohydrin Carbonate Esters
Tetrahedron Letters, 2003Co-Authors: Nopporn Thasana, Vilailak Prachyawarakorn, Sopchok Tontoolarug, Somsak RuchirawatAbstract:A facile synthesis of aryl α-keto Esters is reported involving the rearrangement of aryl cyanohydrin Carbonate Esters induced by the α-carbanion to the nitrile group generated by LDA. However, under similar conditions, an o-benzyloxycyanohydrin Carbonate ester rearranged via a domino reaction leading to 2-phenylbenzofuran-3-carboxylic acid.
Feng Wu - One of the best experts on this subject based on the ideXlab platform.
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A theoretical study on Na+ solvation in Carbonate ester and ether solvents for sodium-ion batteries.
Physical Chemistry Chemical Physics, 2020Co-Authors: Feng Wu, Daobin Mu, Borong WuAbstract:The electrochemical performance of sodium-ion batteries is strongly related to the electrolyte solvents. Na+ solvation in commonly used Carbonate Esters such as ethylene Carbonate (EC), propylene Carbonate (PC), diethyl Carbonate (DEC), dimethyl Carbonate (DMC), and ethyl methyl Carbonate (EMC) as well as in ether solvents such as 1,3-dioxolane (DOL), tetrahydrofuran (THF), and dimethoxyethane (DME) is studied by the density functional theory for sodium-ion batteries. It is indicated that the thermodynamic equilibrium is reached when forming 4sol–Na+ in the EC, PC, DMC, EMC, DEC, and THF solvents by spontaneous stepwise solvation reactions, and the formation of 3sol–Na+ complexes will reach thermodynamic equilibrium in DOL and DME at room temperature. It is demonstrated that Na+ is more easily solvated by the Carbonate ester-based solvents EC, PC, DEC, DMC and EMC compared with that for the ether-based solvents DOL, THF and DME. In addition, the cyclic Carbonate ester solvents more easily form a solvation–Na+ complex compared with the linear Carbonate ester solvents, and THF is the easiest to form the solvation–Na+ complex among the three ether-based solvents. It is also indicated that the CO and Carbonate C–O bond stretching vibrations in Carbonate ester solvation complexes move to higher and lower frequencies, respectively, with the decrease in Na+ concentration. In addition, the C–O stretching vibrations with or without Na+ interactions in the ether solvation complexes shift to higher and lower frequencies, respectively, and the shift in frequency is not obvious after forming the maximum innermost solvation shell.
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Theoretical Studies of the Reduction of Cyclic Esters on the Anode Interface of Lithium Batteries
Journal of The Electrochemical Society, 2017Co-Authors: Qi Liu, Liang Gai, Lili Shi, Daobin Mu, Borong Wu, Hongliang Xu, Lei Wang, Feng WuAbstract:SEI film with a stable structure and uniform morphology is important for lithium ion battery and Li metal battery. Density functional theory (DFT) theory comparative study on the reduction mechanism of cyclic Esters are carried out to deeply analyze the formation, composition, structure, reactivity and stability of SEI film. The reaction activation energy, gibbs free energies, enthalpies and structures of the transition states are calculated. It is demonstrated that ethylene Carbonate (EC), propylene Carbonate (PC) and vinylene Carbonate (VC) could be reduced to form organic species of LiOCH2CH2OLi, LiOCH2(CH3)CHOLi and LiOCHCHOLi respectively, meanwhile release CO gases through two-electron mechanism, the reduction also can produce organic SEI components through one-electron reduction mechanism; the priority of the one-electron and two-electron reductions is in order of VC > EC > PC. The formation of Li2CO3 by two-electron reduction mechanism is more favorable in order of EC > PC > VC. Furthermore, the two-electron reduction for sulfites ethylene sulfite (ES) and 1,3-propylene sulfite (PS) to form Li2SO3 is harder than Carbonates of EC, PC and VC, but the one-electron reduction decomposition of ES and PS binding with Li+ is easier than the Carbonates Esters, indicating that ES and PS are prior to form organic SEI film compared with Carbonate Esters. (C) 2017 The Electrochemical Society. All rights reserved.
Etienne Schact - One of the best experts on this subject based on the ideXlab platform.
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preparation of 4 nitrophenyl Carbonate Esters of poly 5n 2 hydroxyethyl l glutamine and coupling with bioactive agents
Macromolecular Chemistry and Physics, 1992Co-Authors: Anne De Marre, Etienne SchactAbstract:Poly[N-(2-hydroxyethyl)-L-glutamine] (PHEG) is a suitable carrier for the design of macromolecular prodrugs. A method is described for partial conversion of hydroxyl side groups into reactive Carbonate Esters. Activation is achieved through the reaction with 4-nitrophenyl chloroformate. It is shown that during the course of the activation no intra- or intermolecular Carbonate Esters are formed. The content of reactive Carbonates can, for a given set of reaction conditions, be controlled by the amount of chloroformate added. The activated polymer easily reacts with numerous amines. Reaction with a melphalan prodrug and amino-terminated glycosides demonstrated the feasibility of the presently described activation method to prepare macromolecular prodrugs.
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Preparation of 4‐nitrophenyl Carbonate Esters of poly‐ [5N‐(2‐hydroxyethyl)‐L‐glutamine] and coupling with bioactive agents
Macromolecular Chemistry and Physics, 1992Co-Authors: Anne De Marre, Etienne SchactAbstract:Poly[N-(2-hydroxyethyl)-L-glutamine] (PHEG) is a suitable carrier for the design of macromolecular prodrugs. A method is described for partial conversion of hydroxyl side groups into reactive Carbonate Esters. Activation is achieved through the reaction with 4-nitrophenyl chloroformate. It is shown that during the course of the activation no intra- or intermolecular Carbonate Esters are formed. The content of reactive Carbonates can, for a given set of reaction conditions, be controlled by the amount of chloroformate added. The activated polymer easily reacts with numerous amines. Reaction with a melphalan prodrug and amino-terminated glycosides demonstrated the feasibility of the presently described activation method to prepare macromolecular prodrugs.