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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.
T A Krenitsky, and
J V Tuttle, and
W H Miller, and
A R Moorman, and
G F Orr, and
L Beauchamp
June 1991,
Biochemical pharmacology,
T A Krenitsky, and
J V Tuttle, and
W H Miller, and
A R Moorman, and
G F Orr, and
L Beauchamp
February 2002,
The Journal of biological chemistry,
T A Krenitsky, and
J V Tuttle, and
W H Miller, and
A R Moorman, and
G F Orr, and
L Beauchamp
January 2011,
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T A Krenitsky, and
J V Tuttle, and
W H Miller, and
A R Moorman, and
G F Orr, and
L Beauchamp
November 1986,
Federation proceedings,
T A Krenitsky, and
J V Tuttle, and
W H Miller, and
A R Moorman, and
G F Orr, and
L Beauchamp
January 2003,
Journal of medicinal chemistry,
T A Krenitsky, and
J V Tuttle, and
W H Miller, and
A R Moorman, and
G F Orr, and
L Beauchamp
October 1993,
Journal of medicinal chemistry,
T A Krenitsky, and
J V Tuttle, and
W H Miller, and
A R Moorman, and
G F Orr, and
L Beauchamp
January 2008,
Journal of the American Chemical Society,
T A Krenitsky, and
J V Tuttle, and
W H Miller, and
A R Moorman, and
G F Orr, and
L Beauchamp
April 1991,
Nucleic acids research,
T A Krenitsky, and
J V Tuttle, and
W H Miller, and
A R Moorman, and
G F Orr, and
L Beauchamp
March 1995,
Journal of medicinal chemistry,
T A Krenitsky, and
J V Tuttle, and
W H Miller, and
A R Moorman, and
G F Orr, and
L Beauchamp
August 2003,
The Journal of biological chemistry,
