A kinetic study on the chemical cleavage of nucleoside diphosphate sugars

Base-modified UDP-sugars reduce cell surface levels of P-selectin glycoprotein 1 (PSGL-1) on IL-1β-stimulated human monocytes

“…A prerequisite for all three of these hypothetical mechanisms is the cellular uptake of the inhibitors in stable form. In biological media, sugar-nucleotides such as compounds 1 and 2 can be subject to both chemical and enzymatic hydrolysis, due to the presence of several labile bonds, including the glycosidic linkage and the pyrophosphate bond ( Huhta et al 2010 ). Under the standard hydrolytic pathway for UDP-sugars ( Huhta et al 2010 ), the primary degradation product of compound 1 would be expected to be UMP derivative 3 .…”

“…In biological media, sugar-nucleotides such as compounds 1 and 2 can be subject to both chemical and enzymatic hydrolysis, due to the presence of several labile bonds, including the glycosidic linkage and the pyrophosphate bond ( Huhta et al 2010 ). Under the standard hydrolytic pathway for UDP-sugars ( Huhta et al 2010 ), the primary degradation product of compound 1 would be expected to be UMP derivative 3 . Results from our stability assay indicate that, while compound 3 itself is stable in hPBMC suspension over 24 h, compound 1 is indeed partly hydrolyzed into compound 3 , both intra- and extracellularly (Fig.…”

Kinetic and NMR spectroscopic study of the chemical stability and reaction pathways of sugar nucleotides

“…[1,2,5] In chemical reactions, an intramolecular nucleophilic attack occurs under neutral and alkaline conditions. [13][14][15][16][17] A neighbouring HO-group in cis-orientation attacks on the a-phosphate (in this context a refers to the sugar bound phosphate in the pyrophosphate moiety) (Scheme 1). The reaction of 1 results in the formation of glycopyranose 1,2-cyclic monophosphate (3) and uridine 5 0 -monophosphate (5 0 -UMP, 4).…”

“…[6,7] In chemical reactions, the pyrophosphate moiety is the predominant reaction site, and an intramolecular displacement at the phosphate occurs. [15,16] As an evidence of such a reaction, a nucleoside monophosphate (4,4b) is released as the major product (Scheme 2). The neighbouring 4-OH group of the acyclic ribose moiety is believed to be the most probable nucleophile in the reaction.…”

“…The neighbouring 4-OH group of the acyclic ribose moiety is believed to be the most probable nucleophile in the reaction. [15] However, under alkaline conditions, a nucleoside diphosphate (5a,b) is formed as a minor product (Scheme 2). [15,16] A reaction sequence involving a series of keto-enol equilibria, followed by an elimination of the phosphate, similarly to a reaction proposed for a reaction of ribose phosphates, [19] has been tentatively proposed as a mechanism for the formation nucleoside diphosphate.…”