PMID: 11925222Apr 2, 2002Paper

Synthesis of new transglycosidically tethered 5'-nucleotides constrained to a highly biologically relevant profile

The Journal of Organic Chemistry
Michael P Groziak, David W Thomas

Abstract

A new motif for restricting 5'-nucleotides to highly biologically relevant conformations has been developed. The 5',6-oxomethylene transglycosidically tethered versions of uridine 5'-monophosphate and 2'-deoxyuridine 5'-monophosphate (1 and 2, respectively) were synthesized in 10-11 steps from their respective natural nucleoside precursors along routes general to the preparation of tethered versions of a wide variety of 5'-nucleotide-based compounds. In both routes, a shelf-stable 6-hydroxymethyl pyrimidine nucleoside 5'-carboxaldehyde is the key intermediate. It exists in a carbohydrate-like fashion in a cyclic hemiacetal form under aprotic conditions. The phosphorylated cyclic hemiacetals 1 and 2 were isolated as binary mixtures of 5'-diastereomers differing principally in the trajectory of the phosphate group with respect to the carbohydrate. By (1)H NMR, both 1 and 2 were demonstrated to be stable to hydrolysis at ambient temperature in D(2)O solution for at least 2 months. The oxomethylene transglycosidic tether as deployed in 1 and 2 leaves all of the native 5'-nucleotide molecular recognition sites intact while it restricts the framework to a low-energy anti glycosyl conformation and an extended phosphate disposition. Th...Continue Reading

References

Apr 1, 1995·Bioorganic & Medicinal Chemistry·M BjörsneB Classon
Jun 4, 1999·Trends in Pharmacological Sciences·G P Connolly, J A Duley
Nov 24, 1999·Journal of Biomolecular Structure & Dynamics·C B NielsenJ P Jacobsen
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne

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