Nucleotide analogue inhibitors of purine nucleoside phosphorylase.
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.
Krenitsky
T A
TA
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
Tuttle
J V
JV
Miller
W H
WH
Moorman
A R
AR
Orr
G F
GF
Beauchamp
L
L
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000998:Antiviral Agents; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D009711:Nucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000097:blood; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D009711:Nucleotides; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase; D000212:Acyclovir