Synthesis of certain nucleoside methylenediphosphonate sugars as potential inhibitors of glycosyltransferases.

Abstract

The synthesis of alpha-D-glucopyranosyl 1-(methylenediphosphonate) (11), alpha-D-galactopyranosyl 1-(methylenediphosphonate) (14), and alpha-D-mannopyranosyl 1-(methylenediphosphonate) (17) has been accomplished. [(Di-phenoxyphosphinyl)methyl]phosphonic acid (diphenyl-MDP) (5), synthesized by two different procedures, was fused with beta-D-glucopyranose pentaacetate followed by catalytic hydrogenation to give 2,3,4,6-tetra-O-acetyl-alpha-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'-[(alpha-D-glucopyranosylhydroxyphosphinyl)methyl]phosphonate (20). Uridine 5'-[(alpha-D-galactopyranosylhydroxyphosphinyl)methyl] phosphonate (23) and guanosine 5'-[(alpha-D-mannopyranosylhydroxyphosphinyl)methyl]phosphonate (26) were similarly prepared. Using a specific glycoprotein galactosyltransferase (EC 2.4.1.38) assay, uridine 5'-[(alpha-D-galactopyranosylhydroxyphosphinyl)methyl]phosphonate (23) demonstrated competitive inhibition with an apparent Ki of 97 microM. 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.

• Authors: M M Vaghefi, R J Bernacki, W J Hennen, R K Robins
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 30 Issue 8 Pg. 1391-9 (Aug 1987) ISSN: 0022-2623 [Print] United States
• PMID: 3475472 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Diphosphonates
• Hexoses
• Nucleosides
• Hexosyltransferases

Topics

• Animals
• Cell Line
• Chemical Phenomena
• Chemistry
• Diphosphonates (chemical synthesis, pharmacology, therapeutic use)
• Hexoses (chemical synthesis, pharmacology, therapeutic use)
• Hexosyltransferases (antagonists & inhibitors)
• Humans
• Leukemia L1210 (drug therapy)
• Leukemia, Lymphoid (drug therapy)
• Magnetic Resonance Spectroscopy
• Mice
• Molecular Conformation
• Nucleosides (chemical synthesis, pharmacology, therapeutic use)
• Structure-Activity Relationship
• Viruses (drug effects)