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

Chemical Research in Toxicology
A W NichollsJ K Nicholson

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 ...Continue Reading

Citations

Oct 3, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Patrick CamilleriAndrew J Hutt
Jun 9, 2009·Organic & Biomolecular Chemistry·Neil G BerryAndrew V Stachulski
Aug 9, 2003·Nature Reviews. Drug Discovery·Jeremy K Nicholson, Ian D Wilson
May 17, 2019·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Glyn Steventon
Oct 27, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mitsuhiro NishiharaSatoru Asahi
Feb 1, 2020·Organic & Biomolecular Chemistry·Peter R BradshawToby J Athersuch
Nov 28, 2006·Journal of Medicinal Chemistry·Andrew V StachulskiIan D Wilson
Jun 18, 2002·Chemical Research in Toxicology·Kazuki AkiraTakao Hashimoto

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