Alkoxyalkyl
esters of
cidofovir, an acyclic
nucleoside phosphonate, have been shown to have
antiviral activities several orders of magnitude greater than unmodified
cidofovir against cytomegalovirus, herpes simplex virus,
vaccinia,
cowpox,
ectromelia and adenoviruses in vitro.
Hexadecyloxypropyl-cidofovir is orally bioavailable and active in lethal animal models of
vaccinia,
cowpox,
ectromelia and cytomegalovirus. To see if this strategy is also applicable to other acyclic
nucleoside phosphonates, we have converted several phosophonomethoxyethyl
purines and
pyrimidines to their hexadecyloxypropyl, octadecyloxyethyl and oleyloxyethyl
esters and compared their activity against HIV-1 with the activity of the respective unmodified acyclic
nucleoside phosphonates. The hexadecyloxypropyl
esters of phosphonomethoxyethyl-
adenine, phosphonomethoxyethyl-2,6-diaminopurine and phosphonomethoxyethyl-N(6)-cyclopropyl-diaminopurine were 3-5 orders of magnitude more active against HIV-1 in vitro than the parent
nucleotides. The EC(50) values for these compounds were in the 10-20 pM range with selective indexes of 1,250 to >4,000. The acyclic
pyrimidine phosphonates were generally inactive against HIV-1 in vitro. Phosphonomethoxyethyl-
cytosine and phosphonomethoxyethyl-5-fluorocytosine were inactive against HIV-1. Surprisingly, hexadecyloxypropyl-phosphonomethoxyethyl-5-fluorocytosine was active against HIV-1 with a submicromolar EC(50) and a selective index of 174. Esterification of acyclic
nucleoside phosphonates with alkoxyalkyl moieties may represent a general approach for increasing
antiviral activity and selectivity of this class of
antivirals.