NMR and QSAR studies on the transacylation reactivity of model 1β-O-acyl glucuronides. I: design, synthesis and degradation rate measurement

Abstract

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 1β-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 106.6 h. The reactions resulted in mixtures, which predominantly consisted of the desired 1β-O-acyl glucuronides.

3. It was demonstrated that further purification was unnecessary for determination of k_d of the synthetic 1β-O-acyl glucuronides. Degradation rates (k_d) were calculated by following the disappearance of the ¹H-NMR signal from the 1β-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 (1β to 2β 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 t_1/2=0.9 h and 4-propoxy t_1/2=106.6 h.