NUCLEOTIDES .49. SYNTHESIS AND CHARACTERIZATION OF CORDYCEPIN-TRIMER-VITAMIN AND CORDYCEPIN-TRIMER-LIPID CONJUGATES POTENTIAL INHIBITORS OFHIV-1 REPLICATION

The syntheses of biodegradable 2'- and 5'-ester and 2'- and 5'-carbona te conjugates of the antivirally active (2'-5')-3'-deoxyadenylyl-(2'-5 ')-3'-deoxyadenosine (cordycepin-trimer core) with the vitamins, E, D- 2, and A and the lipids 1,2-di-O-palmitoylglycerol and 1,2-di-O-hexade cylglycerol were achieved first by preparation of the trimeric educts 19-21 (Scheme 1). Secondly, these substances were condensed with the l ipophilic residues via a succinate or carbonate linker and then deprot ected by beta-elimination of the npeoc and npe protecting groups and a cid treatment for detritylation without harming the ester and carbonat e functions, respectively (Scheme 2). Metabolically stable cordycepin- trimer-vitamin and -lipid conjugates are a new class of bioconjugates that inhibit HIV-1-induced syncytia formation with IC50 values of 7, 1 8, and 24 mu M for 39, 29, and 42, respectively, and inhibit HIV-1 rev erse transcriptase (RT) activity from 14 to 96% (see Table). OF the ni ne conjugates tested, inhibition of HIV-1 replication by 28, 29, 32, 4 0, and 42 may be attributed in part to the activation of the RNase L/P KR antiviral pathways. Trimer conjugate 42 showed the greatest inhibit ion of HIV-1 replication, i.e., a 120-fold decrease in HIV-1-induced s yncytia formation and an 88% inhibition of HIV-1 reverse transcriptase (RT). This inhibition of replication of HIV-1 by 42 can be attributed in part to the activation of recombinant, human RNase L. The inhibiti on of HIV-1 replication by the cordycepin-trimer-vitamin and -lipid co njugates is significantly greater than that observed for the (2'-5') A -trimer core or cordycepin-trimer core.