Nucleotides. Part IL. Synthesis and Characterization of Cordycepin-Trimer-Vitamin and -Lipid Conjugates Potential Inhibitors of HIV-1 Replication
| Autor: | Marita Wasner, Wolfgang Pfleiderer, Robert J. Suhadolnik, Susan E. Horvath, Ning Kon, Ming-Xu Guan, Earl E. Henderson, Martin E. Adelson |
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| Rok vydání: | 1996 |
| Předmět: |
chemistry.chemical_classification
Cordycepin RNase P Stereochemistry Organic Chemistry Trimer Biochemistry Catalysis Reverse transcriptase law.invention Inorganic Chemistry chemistry.chemical_compound chemistry law Drug Discovery Recombinant DNA Nucleotide Physical and Theoretical Chemistry Linker Conjugate |
| Zdroj: | Helvetica Chimica Acta. 79:619-633 |
| ISSN: | 1522-2675 0018-019X |
| DOI: | 10.1002/hlca.19960790305 |
| Popis: | 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, D2, 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 IC50 values of 7, 18, and 24 mM 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. |
| Databáze: | OpenAIRE |
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