Bioreversible Derivatives of Phenol. 2. Reactivity of Carbonate Esters with Fatty Acid-like Structures Towards Hydrolysis in Aqueous Solutions

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. 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. Molecules 2007, 12 2397

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

“…The hydrolysis rates of the carbonate esters in aqueous buffer (pH 7.40) were found to follow pseudo-first-order kinetics, however, at widely different rates, with half-lives ranging from 31 min to 280 h. The results obtained are in agreement with those previously obtained under slightly different conditions [28]. The stability of the carbonate esters in plasma was monitored for up to 8 h and the degradation reactions were also found to follow pseudo-first-order kinetics ( Table 2).…”

“…Diphenyl carbonate, phenol, p-nitrophenyl acetate, octanoic acid, and t-butyl phenyl carbonate were obtained from Aldrich-Chemie (Steinheim, Germany). 2-(Phenoxycarbonyloxy)-acetic acid, 6-(phenoxycarbonyloxy)-hexanoic acid, 8-(phenoxycarbonyloxy)-octanoic acid, 12-(phenoxycarbonyloxy)-dodecanoic acid, and 16-(phenoxycarbonyloxy)-hexadecanoic acid were synthesized and characterized as described elsewhere [28]. All other chemicals and solvents were of analytical grade or better.…”

“…In the current work, we present the in vitro characterization of a series of carbonate esters of phenol encompassing derivatives with fatty acid-like structures (Table 1) with respect to stability in phosphate buffer (pH 7.40), diluted plasma and rat liver homogenate as well as initial studies on the interaction between the carbonate esters and HSA and the implications hereof on carbonate ester reconversion rates. The synthesis of the carbonate ester derivatives is reported in the accompanying work together with detailed studies on the susceptibility of the carbonate esters towards hydrolysis as a function of pH [28]. In the following, bioreversible derivative is used as the preferred term, since phenol is not a drug and consequently the carbonate esters subject to study not prodrug derivatives.…”

A TFAA–H3PO4-mediated direct, metal-free and high-speed synthesis of aryl carboxylate esters from phenols

“…ArOCOR, 1) are of commercial interest because of their usage as components of liquid crystals and polyarylated liquid crystal polymers [1]. Besides, these esters are of medicinal interest as many of these derivatives have been studied as potential prodrug of phenolic drugs [2,3]. Moreover, Aspirin or acetylsalicylic acid, a well-known anti-inflammatory drug belongs to this class ( Fig.…”

Preparation of mixed trialkyl alkylcarbonate derivatives of etidronic acid via an unusual route

“…One rather straightforward way to improve the lipophilicity of these compounds is to prepare alkyl carbonate derivatives of BPs. Alkyl carbonate derivatives of phenol and naphthols have been reported to undergo chemical and enzymatic hydrolysis [21–22] and so they have been considered as prodrugs, e.g., naltrexone [23–24], which is used for the treatment of alcohol dependence [25] and opioid addiction [26]. This was the starting point for the research project reported here.…”