D. Bonnaffe et al., POTENTIAL LIPOPHILIC NUCLEOTIDE PRODRUGS - SYNTHESIS, HYDROLYSIS, ANDANTIRETROVIRAL ACTIVITY OF AZT AND D4T ACYL NUCLEOTIDES, Journal of organic chemistry, 61(3), 1996, pp. 895-902
Three general methods for the synthesis of acyl nucleotides (mono-, di
-, and triphosphates) have been developed and applied to different HIV
inhibitors. These new types of compounds, where a fatty acid moiety i
s linked to the nucleotide phosphate chain by an acyl phosphate bond,
were designed as lipophilic prodrugs of HIV inhibitors metabolites. Ac
yl nucleoside monophosphates la,b were prepared by acylation of the co
rresponding nucleoside monophosphates. Acyl nucleoside diphosphates 2a
-c and 3a,b were synthesized directly from the free nucleosides using
DCC activation of acyl pyrophosphates. Acyl nucleoside triphosphates 4
a-c and 5a were obtained using phosphoromorpholidate chemistry and acy
l pyrophosphates as nucleophiles. Hydrolysis of acyl nucleotides liber
ated the corresponding nucleotides by selective cleavage of the acyl p
hosphate bond, with half lives ranging from 51 to 185 h at 37 degrees
C in triethylammonium acetate buffer pH 7.0. Their antiretroviral acti
vity, measured by the inhibition of cytopathogenicity and reverse tran
scriptase activity in the cultures supernatants, did not reveal any di
fferences between an acyl nucleotide and its corresponding nucleotide.
These results are explained in term of rapid aminolysis of the acyl p
hosphate bond in culture media.