NUCLEOTIDES .44. SYNTHESIS, CHARACTERIZATION, AND BIOLOGICAL-ACTIVITYOF MONOMERIC AND TRIMERIC CORDYCEPIN-CHOLESTEROL CONJUGATES AND INHIBITION OF HIV-1 REPLICATION

The antivirally active 3'-deoxyadenylyl-(2'-5 ')-3 '-deoxpadenylyl (2' -5')-3'-deoxyadenosine (cordycepin trimer core) was modified at the 2' - or 5'-terminus, by attachment of cholesterol via a carbonate bond (- -> 15) or a succinate linker (--> 16 and 27) to improve cell permeabil ity. The corresponding monomeric conjugates 4, 7, and 21 of cordycepin were prepared as model substances to study the applicability of the a nticipated protecting groups the monomethoxytrityl (MeOTr), the (tert- butyl)dimethylsilyl(tbds), and the beta-eliminating 2-(4-nitrophenyl)e thyl (npe) and 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) groups - for th e final deblocking steps without harming the ester bonds of the conjug ate trimers. The syntheses were performed in solution using phosphoram idite chemistry. The fully protected trimer conjugates 13, 14, and 26 as well as all intermediates were characterized by elemental analyses, UV and H-1-NMR spectra. The deblocked conjugates 15, 16, and 27 were pure according to HPLC and showed the correct compositions by mass spe ctra. Comparative biological studies indicated that cordycepin-cholest erol conjugate trimers 16 and 27 were 333- and 1000-fold, respectively , more potent inhibitors of HIV-1-induced syncytia formation than cord ycepin trimer core.