Glycosylation of aromatic amines II: Kinetics and mechanisms of the hydrolytic reaction between kynurenine and glucose

Abstract

The kinetics of the weakly basic aromatic amine, kynurenine, with glucose were studied as model reactants aimed at mechanistic understanding of pharmaceutically relevant amine-aldehyde reactions. The reaction kinetics of the forward and reverse processes (glycosylamine formation and hydrolysis) were studied under first-order conditions in aqueous solutions at 40°C in the pH range 1–6.5 in the presence of various buffers. The α-and β-glycosylamines were reversibly formed via an acyclic imine that was not present in detectable quantities. Rate-limiting formation of the imine was complex and involved the addition of the amine and aldehyde to form the carbinolamine followed by the acid-catalyzed dehydration to the imine. The pH-rate profile was characterized by three kinetically distinguishable processes. At lower pH values, the profile was consistent with specific acid-catalyzed rate-determining addition of amine and aldehyde. In the pH range of 4–6 a downward bend was attributable to the change in rate determining step from addition to dehydration. In the pH region of 2–3 the rate law was described by specific acid catalysis and solvolysis of the zwitterionic form of kynurenine. Nonlinear buffer effects and Brönsted plots were shown to be consistent with this interpretation of the pH-rate profile. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4616–4628, 2009