Article

Synthesis and antiviral evaluation of 9-(S)-[3-alkoxy-2-(phosphonomethoxy)propyl]nucleoside alkoxyalkyl esters: inhibitors of hepatitis C virus and HIV-1 replication.

Division of Infectious Diseases, University of California, San Diego, USA.
Bioorganic & medicinal chemistry (impact factor: 2.82). 06/2011; 19(15):4616-25. DOI:10.1016/j.bmc.2011.06.009 pp.4616-25
Source: PubMed

ABSTRACT We reported previously that octadecyloxyethyl 9-(S)-[3-hydroxy-2-(phosphonomethoxy)-propyl]adenine (ODE-(S)-HPMPA) was active against genotype 1b and 2a hepatitis C virus (HCV) replicons. This is surprising because acyclic nucleoside phosphonates have been regarded as having antiviral activity only against double stranded DNA viruses, HIV and HBV. We synthesized octadecyloxyethyl 9-(S)-[3-methoxy-2-(phosphonomethoxy)propyl]-adenine and found it to be active in genotype 1b and 2a HCV replicons with EC₅₀ values of 1-2 μM and a CC₅₀ of > 150 μM. Analogs with substitutions at the 3'-hydroxyl larger than methyl or ethyl, or with other purine bases were less active but most compounds had significant antiviral activity against HIV-1 in vitro. The most active anti-HIV compound was octadecyloxyethyl 9-(R)-[3-methoxy-2-(phosphonomethoxy)propyl]guanine with an EC₅₀ < 0.01 nanomolar and a selectivity index of > 4.4 million.

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Keywords

2a HCV replicons
 
active
 
active anti-HIV compound
 
acyclic nucleoside phosphonates
 
antiviral activity
 
DNA viruses
 
EC₅₀ values
 
genotype 1b
 
methyl
 
octadecyloxyethyl 9-(S)-[3-hydroxy-2-(phosphonomethoxy)-propyl]adenine
 
purine bases
 
substitutions
 
vitro