Synthesis and biological evaluation of 9-(5′,5′-difluoro-5′-phosphonopentyl)guanine derivatives for PNP-inhibitors

9-(5′,5′-Difluoro-5′-phosphonopentyl)guanine and its hypoxanthin analogue were modified by introducing a methyl group to all possible positions (α- to γ-position) of the linker connecting a purine and a difluoromethylenephosphonic acid moiety to evaluate the effects of the methyl group on inhibition against purine nucleoside phosphorylase. 9-(5′,5′-Difluoro-5′-phosphonopentyl)guanine ( DFPP- G) and its hypoxanthine analogue ( DFPP- H) were modified by introducing a methyl group to all possible positions of the linker connecting a purine and difluoromethylenephosphonic acid moiety to evaluate the effects of the methyl group on inhibition against purine nucleoside phosphorylase. The methyl group on the linker affected the inhibition in a positional-dependent manner. Inhibitory potency of α-methyl and β-methyl-substituted analogues of DFPP- H increased by about 600- to 1000-fold upon converting to cyclopropane nucleotide analogue (±)- 4.