Synthesis of New Transglycosidically Tethered 5‘-Nucleotides Constrained to a Highly Biologically Relevant Profile
| Autor: | Michael P. Groziak, David W. Thomas |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Magnetic Resonance Spectroscopy
Pyrimidine Uracil Nucleotides Stereochemistry Ribose Chemistry Organic Molecular Conformation Crystallography X-Ray Ligands Structure-Activity Relationship chemistry.chemical_compound Deoxyribonucleotide Molecular recognition Nucleotide Glycosyl chemistry.chemical_classification Molecular Structure Hydrolysis Molecular Mimicry Organic Chemistry computer.file_format Protein Data Bank chemistry Cyclization computer Nucleoside Uracil nucleotide |
| Zdroj: | The Journal of Organic Chemistry. 67:2152-2159 |
| ISSN: | 1520-6904 0022-3263 |
| DOI: | 10.1021/jo0110045 |
| Popis: | 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. This provides a spatial presence that approximates nearly three-quarters of the protein-bound 5'-nucleotide ligands described in the Protein Data Bank. The tether has a low structural and electronic impact, occupies a region of space (over the beta-face of the furan ring) seldom penetrated by proteins, and should be accommodated as readily on purine-based 5'-nucleotide frameworks as on pyrimidine-based ones. Because of its unique and attractive features, this new motif for the conformational restriction of 5'-nucleotides is expected to be useful for producing probes of structure/function relationships and in assessing the conformational binding requirements that enzymes and receptor sites have for their natural 5'-nucleotide-based ligands. |
| Databáze: | OpenAIRE |
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