Synthesis of new transglycosidically tethered 5'-nucleotides constrained to a highly biologically relevant profile.
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.
Groziak
Michael P
MP
SRI International, 333 Ravenswood Ave., Menlo Park, California 94025-3493, USA. michael.groziak@sri.com
Thomas
David W
DW
D002625:Chemistry, Organic / Q000379:methods; D018360:Crystallography, X-Ray; D003500:Cyclization; D006868:Hydrolysis; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D018716:Molecular Mimicry; D015394:Molecular Structure; D012266:Ribose / Q000737:chemistry; D013329:Structure-Activity Relationship; D014500:Uracil Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry
D008024:Ligands; D014500:Uracil Nucleotides; D012266:Ribose