NUCLEOSIDES .60. SYNTHESIS AND CHARACTERIZATION OF MONOMERIC CORDYCEPIN-VITAMIN AND CORDYCEPIN-LIPID CONJUGATES MODEL SUBSTANCES FOR BIODEGRADABLE ESTER AND CARBONATE LINKAGES IN CONJUGATES AND POTENTIAL INHIBITORS OF HIV-1 REPLICATION

Monomeric 3'-deoxyadenosine (cordycepin) was modified at the 2'-O-(13- 18) and 5'-O-position (25-29) by the vitamins E, D-2, and A and by the two lipids 1,2-di-O-palmitoylglycerol and 1,2-di-O-hexadecylglycerol via succinate or carbonate linkages. These base-labile conjugates affo rded protection groups like the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc ) and monomethoxytrityl group (MeOTr) that are cleavable without harmi ng the ester and carbonate bonds, respectively. Monomeric conjugates o f cordycepin and vitamin E, vitamin D-2, 1,2-di-O-palmitoylglycerol, a nd 1,2-di-O-hexadecylglycerol (see 13, 14, 17, 18, 25, 26, 28, and 29) inhibited HIV-1-induced syncytia formation 1.7 to 6.2 fold compared t o 1.5-fold for cordycepin (see Table); IC50 values for 25 and 28 were 257 and 267 mu M, respectively. In addition, the monomeric cordycepin- vitamin and -lipid conjugates inhibited HIV-1 RT activity 28-49% which compares with a 13% inhibition of HIV-1 RT observed for cordycepin. T he minimal inhibition of HIV-1-induced syncytia formation and HIV-1 RT activity did not proceed by the activation of RNase L. The monomeric conjugates tested (13, 14) increased PKR expression.