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-octadec yl-2-X-sn-glycero-3-PFA were synthesized and evaluated for antiviral a ctivity in HCMV-infected human lung fibroblasts (X is -H, -OH or an O- alkyl group of increasing chain length) in order to study structure-ac tivity 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 an alogs were 1.96, 0.36 1.0, 0.7, 0.53 and 0.18 mu M respectively versus 40 mu M for PFA, representing increases in antiviral activity of 20-2 20 fold. We also synthesized the enantiomer of ODG-PFA, 3-O-octadecyl- sn-glycero-1-PFA, and found that the antiviral activity of both enanti omers as well as the racemate were not significantly different, with E C50 values in the range of 0.67-0.71 mu M. (C) 1997 Elsevier Science B .V.