Structure-activity relationships for degradation reaction of 1-beta-o-acyl glucuronides: kinetic description and prediction of intrinsic electrophilic reactivity under physiological conditions

Chem Res Toxicol. 2009 Jan;22(1):158-72. doi: 10.1021/tx800292m.


1-beta-O-Acyl glucuronides (betaGAs) are potentially reactive metabolites capable of binding to proteins, and they have been implicated in adverse drug reactions of the carboxylic acid drugs. To explore their electrophilic reactivity, we studied structure-activity relationships (SARs) to characterize the factors affecting the degradation rate constants (k values) of betaGAs and ultimately to predict k values of structurally diverse betaGAs. Twenty-seven betaGAs and four related compounds were synthesized, and their k values were determined under physiological conditions (pH 7.4 and 37 degrees C). 1-beta-O-Benzoyl glucuronide (BAGA) and glucopyranoside (BAG) showed almost the same k values, whereas their 1-alpha-O-benzoyl isomers degraded approximately 40-fold faster than BAGA and BAG. BAGA methyl ester showed almost the same rate constant as BAGA in the cleavage of their 1-beta-O-benzoyl linkages. A pH-log k profile obtained indicated kinetics catalyzed by both specific and general bases. The log k of betaGAs derived from m- and p-substituted benzoic acids correlated with Hammett's sigma constants. A similar correlation was observed with delta(COOH), (1)H NMR chemical shifts of the parent benzoic acids including ones with less sterically bulky o-substituents. Alternative descriptors of delta(CO) and delta((CO)OH), (13)C chemical shifts for ester carbonyl carbons of betaGAs and for carbonyl carbons of the parent benzoic acids, respectively, correlated well with the log k of all 16 betaGAs derived from benzoic acids including ones with bulkier o-substituents. Of the betaGA isomers derived from (2R)- and (2S)-alpha-methyl-4-biphenylylacetic acid, the (2R)-isomer degraded approximately 2-fold faster than the (2S)-isomer. The alpha-methyl group in the (2S)-isomer would encumber the intramolecular acyl migration. The log k of betaGAs derived from n-aralkyl carboxylic acids and of the (2R)-isomer correlated with their delta(COOH). However, the log k of betaGAs derived from alpha,alpha-dimethyl- and alpha,alpha-diethyl-4-biphenylylacetic acids deviated downward from the regression line, probably due to a steric effect. The diversity and complexity of k values were discussed with respect to the electrophilicity of the ester carbonyl carbons of betaGAs and the steric hindrance around them.

MeSH terms

  • Glucuronides / chemical synthesis
  • Glucuronides / chemistry*
  • Glucuronides / toxicity
  • Kinetics
  • Proteins / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship


  • Glucuronides
  • Proteins