Synthesis and antiviral activity of 1-O-octadecyl-2-O-alkyl-sn-glycero-3-foscarnet conjugates in human cytomegalovirus-infected cells.

A series of new lipid prodrugs with the general structure, 1-O-octadecyl-2-X-sn-glycero-3-PFA were synthesized and evaluated for antiviral activity in HCMV-infected human lung fibroblasts (X is -H, -OH or an O-alkyl group of increasing chain length) in order to study structure-activity relationships of PFA lipid prodrugs. The EC50 values for the 2-O-octyl, 2-O-butyl, 2-H, 2-OH, 2-O-methyl and 2-O-ethyl substituted analogs were 1.96, 0.36, 1.0, 0.7, 0.53 and 0.18 microM respectively versus 40 microM for PFA, representing increases in antiviral activity of 20-220 fold. We also synthesized the enantiomer of ODG-PFA, 3-O-octadecyl-sn-glycero-1-PFA, and found that the antiviral activity of both enantiomers as well as the racemate were not significantly different, with EC50 values in the range of 0.67-0.71 microM.