Premium
Nucleotides. Part IL. Synthesis and Characterization of Cordycepin‐Trimer‐Vitamin and ‐Lipid Conjugates Potential Inhibitors of HIV‐1 Replication
Author(s) -
Wasner Marita,
Pfleiderer Wolfgang,
Suhadolnik Robert J.,
Horvath Susan E.,
Kon Ning,
Guan MingXu,
Henderson Earl E.,
Adelson Martin E.,
Henderson Earl E.,
Suhadolnik Robert J.
Publication year - 1996
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.19960790305
Subject(s) - chemistry , trimer , reverse transcriptase , linker , stereochemistry , conjugate , biochemistry , rna , dimer , organic chemistry , mathematical analysis , mathematics , gene , computer science , operating system
The syntheses of biodegradable 2′‐ and 5′ ‐ester and 2′‐ and 5′ ‐carbonate conjugates of the antivirally active 3′‐deoxyadenylyl‐(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 ‐hexadecylglycerol were achieved first by preparation of the trimeric educts 19–21 ( Scheme 1 ). Secondly, these substances were condensed with the lipophilic residues via a succinate or carbonate linker and then deprotected by β‐elimination of the npeoc and npe protecting groups and acid treatment for detritylation without harming the ester and carbonate 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 IC 50 values of 7, 18, and 24 m̈ M for 39, 29 , and 42 , respectively, and inhibit HIV‐1 reverse transcriptase (RT) activity from 14 to 96% (see Table ). Of the nine conjugates tested, inhibition of HIV‐1 replication by 28, 29, 32, 40 , and 42 may be attributed in part to the activation of the RNase L/PKR antiviral pathways. Trimer conjugate 42 showed the greatest inhibition of HIV‐1 replication, i.e. , a 120‐fold decrease in HIV‐1‐induced syncytia 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 inhibition of HIV‐1 replication by the cordycepin‐trimer‐vitamin and ‐lipid conjugates is significantly greater than that observed for the (2′–5′) A‐trimer core or cordycepin‐trimer core.