title: NMR spectroscopic and theoretical chemistry studies on the internal acyl migration reactions of the 1-O-acyl-beta-D-glucopyranuronate conjugates of 2-, 3-, and 4-(trifluoromethyl) benzoic acids.
abstract: High resolution 19F NMR spectroscopy has been used to investigate the kinetics of internal acyl migration and hydrolysis of the synthetic beta -1-O-acyl-D-glucopyranuronates of 2-, 3-, and 4-(trifluoromethyl) benzoic acids (TFMBAs) in phosphate buffer solutions at 30 degrees C as models of drug ester glucuronides. Apparent first-order degradation of the 1-O-acyl glucuronide and the sequential appearance of 2-, 3-, and 4-O-acyl isomers as both alpha- and beta-anomeric forms were observed for each TFMBA isomer. The overall degradation rate constants of the 2-, 3-, and 4-TFMBA 1-O-acyl isomers were 0.065 h-1, 0.25 h-1, and 0.52 h-1. In order to probe the reasons for these differences in reactivity, theoretical structural and electronic parameters for the beta-anomers of the 1-O-acyl glucuronides, their beta-2-O-acyl isomers, and both structures of the postulated ortho-acid ester intermediate were computed using semiempirical molecular orbital (AM1 and PM3) methods. The distinction between the slowly reacting 2-TFMBA glucuronide and the much faster reacting 3- and 4-TFMBA glucuronides could be observed by calculation of the relative bond order of the C-O bonds in the ortho-acid ester intermediates. The slow internal acyl migration rate of the 2-TFMBA isomer was also partly attributed to the high degree of steric hindrance of the trifluoromethyl group obstructing attack by the glucuronic acid 2-hydroxy group on the carbonyl carbon to form the ortho-acid ester intermediate. Some calculated molecular orbital properties, namely, dipole moment, energy of the lowest unoccupied molecular orbital (LUMO), LUMO density, and nucleophilic frontier density on the carbonyl carbon, were also shown to be related to the measured half-lives. This work gives insight into the molecular physicochemical properties that influence the acyl migration kinetics of simple model drug glucuronides and is of potential importance in understanding more complex drug glucuronide acyl migration reactions of toxicological interest.
authors.affiliation: Department of Chemistry, Birbeck College, University of London, U.K.
authors.forename: A W
authors.initials: AW
authors.lastname: Nicholls
authors.forename: K
authors.initials: K
authors.lastname: Akira
authors.forename: J C
authors.initials: JC
authors.lastname: Lindon
authors.forename: R D
authors.initials: RD
authors.lastname: Farrant
authors.forename: I D
authors.initials: ID
authors.lastname: Wilson
authors.forename: J
authors.initials: J
authors.lastname: Harding
authors.forename: D A
authors.initials: DA
authors.lastname: Killick
authors.forename: J K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D000215:Acylation; D001565:Benzoates / Q000737:chemistry*; D002021:Buffers; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D005965:Glucuronates / Q000737:chemistry; D006207:Half-Life; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011134:Polysaccharides / Q000737:chemistry*; D011485:Protein Binding; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D001565:Benzoates; D002021:Buffers; D005965:Glucuronates; D011134:Polysaccharides