Synthesis of certain nucleoside methylenediphosphonate sugars as potential inhibitors of glycosyltransferases

Article abstract of DOI:10.1021/jm00391a021

The synthesis of α-D-glucopyranosyl 1-(methylenediphosphonate) (11), α-D-galactopyranosyl 1-(methylenediphosphonate) (14), and α-D-mannopyranosyl 1-(methylenediphosphonate) (17) has been accomplished. [(Diphenoxyphosphinyl)methyl]phosphonic acid (diphenyl-MDP) (5), synthesized by two different procedures, was fused with β-D-glucopyranose pentaacetate followed by catalytic hydrogenation to give 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl methylenediphosphonate (glucose-MDP) (10). The anomeric configuration of 10 was assigned on the basis of NMR spectral studies. Condensation of 10 with 2',3'-di-O-acetyladenosine was accomplished by using 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT) as coupling agent, and removal of the blocking groups gave adenosine 5'-[(α-D-glucopyranosylhydroxyphosphinyl)methyl]phosphonate (20). Uridine 5'-[(α-D-galactopyranosylhydroxyphosphinyl)methyl]phosphonate (23) and guanosine 5'-[(α-D-mannopyranosylhydroxyphosphinyl)methyl]phosphonate (26) were similarly prepared. Using a specific glycoprotein galactosyltransferase (EC 2.4.1.38) assay, uridine 5'-[(α-D-galactopyranosylhydroxyphosphinyl)methyl]phosphonate (23) demonstrated competitive inhibition with an apparent K(i) of 97 μM. The adenosine analogue did not inhibit the enzyme. None of the above compounds show any in vitro antitumor or antiviral activity. Such specific inhibitors of glycosyltransferases may serve as specific probes to study various glycosyltransferases that might be involved in the process of metastasis.