NMR and QSAR studies on the transacylation reactivity of model 1beta-O-acyl glucuronides. I: design, synthesis and degradation rate measurement.
1. The products arising from intramolecular acyl migration reactions of drug ester glucuronides are reactive towards cellular proteins and can potentially cause toxic side-effects. The relationship between molecular structure and the degradation rates (kd) of 1beta-O-acyl glucuronides were investigated systematically using a series of model compounds based on 4-substituted benzoic acids. 2. A rational method for selecting suitable compounds for inclusion was used and 10 glucuronide esters, predicted to produce a wide range of transacylation rates, were synthesized via a simple "one-pot" method using an imidazolide intermediate. The 10 substituents, where X = NO2, CN, I, Br, F, H, nPr, Et, OMe, O-nPr, had degradation rate half-lives (t1/2 = loge(2)/kd) ranging from 0.9 to 106.6 h. The reactions resulted in mixtures, which predominantly consisted of the desired 1beta-O-acyl glucuronides. 3. It was demonstrated that further purification was unnecessary for determination of kd of the synthetic 1beta-O-acyl glucuronides. Degradation rates (kd) were calculated by following the disappearance of the 1H-NMR signal from the 1beta-anomeric proton of the glucuronic acid moiety as the reaction progressed in pH 7.4 buffer inside an nuclear magnetic resonance tube. Each measured degradation rate represents a pseudo-first-order rate constant, which is a combination of the transacylation rate (1beta to 2beta isomer) and the hydrolysis rate. 4. Degradation rates show a clear relationship with substituent properties, with half-life increasing as the substituent becomes more electron-donating, e.g. 4-nitro t1/2 = 0.9 h and 4-propoxy t1/2 = 106.6 h.
Vanderhoeven
S J
SJ
Biological Chemistry, Biological Sciences Division, Sir Alexander Fleming Building, Imperial College, London, SW7 2AZ, UK.
Lindon
J C
JC
Troke
J
J
Tranter
G E
GE
Wilson
I D
ID
Nicholson
J K
JK
D000215:Acylation; D001565:Benzoates / Q000737:chemistry; D020719:Glucuronides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D021281:Quantitative Structure-Activity Relationship
D001565:Benzoates; D020719:Glucuronides