ABSTRACT
The synthesis of new class of potential TPase inhibitors containing a difluoromethylphosphonate function as phosphate mimic is reported. This new series was prepared from a readily available fluorinated building block in few steps. Two series were evaluated as potential inhibitors: a linear series and a conformational constrained series. The activity of these multisubstrate inhibitors depends on the size of the spacer introduced between the pyrimidine ring and the phosphonate function. Best results were observed from triazolyl derivatives, easily obtained from propargylthymine and corresponding azides.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Nucleosides/chemical synthesis , Organophosphonates/chemical synthesis , Thymidine Phosphorylase/antagonists & inhibitors , Angiogenesis Inhibitors/chemistry , Crystallography, X-Ray , Escherichia coli/enzymology , Models, Molecular , Molecular Conformation , Molecular Structure , Nucleosides/chemistry , Organophosphonates/chemistry , Structure-Activity Relationship , Substrate Specificity , Thymidine Phosphorylase/chemistryABSTRACT
Preparation of several acyclonucleosides containing both a difluoromethylphosphonate group and a triazole moiety is described starting from a difluorophosphonosulfide. The key step of the synthesis involves a copper(I)-catalyzed Huisgen 1-3 dipolar cycloaddition between difluorophosphonylated azides and propargylated nucleobases derived from thymine and 2-amino-6-chloropurine.
Subject(s)
Copper/chemistry , Nucleotides/chemistry , Nucleotides/chemical synthesis , Organophosphonates/chemistry , Alkynes/chemistry , CatalysisABSTRACT
Ring-opening reactions of functionalized 1,2-cyclic sulfates and oxetanes with the phosphonodifluoromethyl carbanion are reported. This approach allows an easy access to fluorinated beta-hydroxyphosphonates that are building blocks in the synthesis of acyclic nucleosides. Synthesis of precursors of nucleoside phosphorylase inhibitors from these alcohols is described.
