NMR and QSAR studies on the transacylation reactivity of model 1β-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 (k(d)) 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 (t(1/2)=log(e)(2)/k(d)) ranging from 0.9 to 106.6h. 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 k(d) of the synthetic 1beta-O-acyl glucuronides. Degradation rates (kd) were calculated by following the disappearance of the H-1-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 e I ectron-donating, e.g. 4-nitro t(1/2) = 0.9 h and 4-propoxy t(1/2) = 106.6 h.