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Nucleotides. Part XLIV . Synthesis, characterization, and biological activity of monomeric and trimeric cordycepin‐cholesterol conjugates and inhibition of HIV‐1 replication
Author(s) -
Wasner Marita,
Pfleiderer Wolfgang,
Henderson Earl E.,
Suhadolnik Robert J.
Publication year - 1994
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19940770707
Subject(s) - chemistry , trimer , conjugate , pentamer , monomer , phosphoramidite , stereochemistry , linker , nucleoside , combinatorial chemistry , dimer , organic chemistry , biochemistry , oligonucleotide , dna , mathematical analysis , mathematics , computer science , operating system , polymer
The antivirally active 3′‐deoxyadenylyl‐(2′–5′)‐3′‐deoxyadenylyl‐(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 permeability. The corresponding monomeric conjugates 4 , 7 , and 21 of cordycepin were prepared as model substances to study the applicability of the anticipated protecting groups – the monomethoxytrityl (MeOTr), the ( tert ‐butyl)dimethylsilyl (tbds), and the β ‐eliminating 2‐(4‐nitrophenyl)ethyl (npe) and 2‐(4‐nitrophenyl)ethoxycarbonyl (npeoc) groups – for the final deblocking steps without harming the ester bonds of the conjugate trimers. The syntheses were performed in solution using phosphoramidite chemistry. The fully protected trimer conjugates 13 , 14 , and 26 as well as all intermediates were characterized by elemental analyses, UV and 1 H‐NMR spectra. The deblocked conjugates 15 , 16 , and 27 were pure according to HPLC and showed the correct compositions by mass spectra. Comparative biological studies indicated that cordycepincholesterol conjugate trimers 16 and 27 were 333‐ and 1000‐fold, respectively, more potent inhibitors of HIV‐1‐induced syncytia formation than cordycepin trimer core.