J. Biol. Chem., Vol. 265, Issue 6, 3066-3069, Feb, 1990
Nucleotide analogue inhibitors of purine nucleoside phosphorylase
TA Krenitsky, JV Tuttle, WH Miller, AR Moorman, GF Orr and L Beauchamp
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
The diphosphate of the antiherpetic agent acyclovir [9-[(2-
hydroxyethoxy)methyl]guanine] has been shown to inhibit purine nucleoside
phosphorylase with unique potency (Tuttle, J. V., and Krenitsky, T. A.
(1984) J. Biol. Chem. 259, 4065-4069). A major factor contributing to the
superior inhibition by this diphosphate over the corresponding mono- and
triphosphates is revealed here. Homologues of acyclovir mono- and
diphosphate that extend the ethoxy moiety by one to four methylene groups
were synthesized. These homologues were evaluated for their ability to
inhibit human purine nucleoside phosphorylase. Within the diphosphate
series, the Ki values increased progressively with increasing chain length.
With the monophosphates, the Ki values reached a minimum with the homologue
containing a pentoxy moiety. A plot of chain length versus Ki values for
both mono- and diphosphates showed that both series had similar optimal
distances between the aminal carbon and the terminal oxygen anion.
Monophosphates with optimal positioning were somewhat less potent than
diphosphates with similar positioning. Nevertheless, it was clear that a
major factor in determining potency of inhibition was the distance of the
terminal phosphate from the guanine moiety.
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