Synthesis, antiviral activity, cytotoxicity and cellular pharmacology of l-3′-azido-2′,3′-dideoxypurine nucleosides

• Published in: European journal of medicinal chemistry Vol. 46; no. 9; pp. 3832 - 3844
• Main Authors: Zhang, Hong-wang, Detorio, Mervi, Herman, Brian D., Solomon, Sarah, Bassit, Leda, Nettles, James H., Obikhod, Aleksandr, Tao, Si-jia, Mellors, John W., Sluis-Cremer, Nicolas, Coats, Steven J., Schinazi, Raymond F.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Masson SAS 01-09-2011; Elsevier
• Subjects: 3′-Azido purine nucleosides; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Glycosylation; HBV; Hepatitis B virus - drug effects; HIV; HIV-1 - drug effects; Humans; Kinetics; l-Nucleoside analogs; Magnetic Resonance Spectroscopy; Medical sciences; Microbial Sensitivity Tests; Microwaves; Models, Molecular; Nucleosides - chemical synthesis; Nucleosides - pharmacology; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - pharmacology; Spectrometry, Mass, Electrospray Ionization; 3′-Azido purine nucleosides; l-Nucleoside analogs; Antiviral agents; HIV; HBV; Purine nucleoside; HIV-1 virus; Organic azide; Orthohepadnavirus; Retroviridae; Cytotoxicity; Pharmacology; Lentivirus; In vitro; Virus; Hepadnaviridae; Dideoxynucleoside; 3'-Azido purine nucleosides; Nucleoside analog; Antiviral; Human immunodeficiency virus; Hepatitis B virus; Chemical synthesis; L-Nucleoside analogs
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2011.05.051

Microwave-assisted optimized transglycosylation reactions were used to prepare eleven modified
l-3′-azido-2′,3′-dideoxypurine nucleosides. These
l-nucleoside analogs were evaluated against HIV and hepatitis B virus. The
l-3′-azido-2′,3′-dideoxypurines nucleosides were metabolized to nucleoside 5′-triphosphates in primary human lymphocytes, but exhibited weak or no antiviral activity against HIV-1. The nucleosides were also inactive against HBV in HepG2 cells. Pre-steady state kinetic experiments demonstrated that the
l-3′-azido-2′,3′-dideoxypurine triphosphates could be incorporated by purified HIV-1 reverse transcriptase, although their catalytic efficiency (
k
pol/
K
d) of incorporation was low. Interestingly, a phosphoramidate prodrug of
l-3′-azido-2′,3′-dideoxyadenosine exhibited anti-HIV-1 activity without significant toxicity.
[Display omitted] A series of
l-3′-azido-2′,3′-dideoxypurine nucleosides were prepared via microwave-assisted transglycosylation and evaluated against HIV and hepatitis B virus. Interestingly, a phosphoramidate prodrug of
l-3′-azido-2′,3′-dideoxyadenosine exhibited anti-HIV-1 activity without significant toxicity.
►Microwave transglycosylation prepared
l-3′-azido-2′,3′-dideoxypurine nucleosides. ►The L-nucleosides had weak or no antiviral activity against HIV-1 and HBV. ►Pre-steady-state kinetics and cellular pharmacology clarified the results. ►An
l-nucleoside phosphoramidate had anti-HIV-1 activity without significant toxicity.