Structure-activity relationships for the degradation reaction of 1-beta-O-acyl glucuronides. Part 3: Electronic and steric descriptors predicting the reactivity of aralkyl carboxylic acid 1-beta-O-acyl glucuronides.
Since 1-beta-O-acyl glucuronides (betaGAs) are thought to be chemically reactive metabolites capable of binding to tissue proteins, possibly leading to adverse drug reactions of the parent carboxylic acid drugs, we have initiated research efforts to derive structure-activity relationships (SARs) of betaGAs, with a focus on finding appropriate descriptors that predict their intrinsic electrophilic reactivity or degradation rate constants (k values). Our previous SAR studies on the k values of betaGAs derived from o-, m-, and p-substituted benzoic acids demonstrated that the diversity and complexity of the k values were controlled by the electronic and/or steric effects of the parent carboxylic acids. In the present study, we performed further SAR studies on the k values of 13 betaGAs derived from aralkyl carboxylic acids, focusing on the substituents and stereochemistry at the alpha-position of the parent carboxylic acids. In single regression analyses, the pKa and (1)H NMR chemical shifts (delta(COOH)) of the parent carboxylic acids correlated well with the log k values of seven betaGAs derived from five arylacetic and two (R)-2-arylpropionic acids, whereas the (13)C NMR chemical shifts [delta(C horizontal lineO) and delta((C horizontal lineO)OH)] correlated with the log k values of another seven betaGAs derived from the five arylacetic and two (S)-2-arylpropionic acids. Excellent correlations were also obtained between the log k values of four betaGAs with a common 4-phenylbenzyl moiety and the partial atomic charges (natural type) of the corresponding carboxylic hydrogen atoms (Hpac), the molar volume (MV), and the molar refractivity (MR). In multiple regression analyses, appropriate combinations of electronic (delta(COOH) or pKa) and steric [Taft's steric constant (Es) or delta((C horizontal lineO)OH)] descriptors could predict the log k values of betaGAs; electron-withdrawing 1-beta-O-acyl groups increased the k values, while increasing steric hindrance around the linkages decreased them. The standard partial regression coefficients indicated that the steric effects of the 1-beta-O-acyl groups of betaGAs affected the k values as strongly as the electronic effects. External validation of the derived SAR models is also discussed.
Baba
Akiko
A
Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan.
Yoshioka
Tadao
T
D020719:Glucuronides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D007536:Isomerism; D007700:Kinetics; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry; D012044:Regression Analysis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D020719:Glucuronides; D011506:Proteins