Adenosine Dioxolane Nucleoside Phosphoramidates As Antiviral Agents for Human Immunodeficiency and Hepatitis B Viruses

Abstract

There are currently six nucleoside reverse transcriptase inhibitors (NRTI) that are FDA approved for human clinical use and these remain the backbone of current HIV therapy. In order for these NRTIs to be effective they need to be phosphorylated consecutively by cellular kinases to their triphosphate forms. Herein, we report the synthesis of C-6 modified (-)-β-D-(2<i>R</i>,4<i>R</i>)-1,3-dioxolane adenosine nucleosides and their nucleotides including our novel phosphoramidate prodrug technology. We have introduced a side chain moiety on the phenol portion of the phosphoramidate to reduce the toxicity potential. The synthesized phosphoramidates displayed up to a 3,600-fold greater potency <i>versus</i> HIV-1 when compared to their corresponding parent nucleoside and were up to 300-fold more potent <i>versus</i> HBV. No cytotoxicity was observed up to 100 μM in the various cell systems tested, except for compound <b>17</b> and <b>18</b> which displayed a CC₅₀ of 7.3 and 12 μM respectively in Huh-7 cells. The improved and significant dual antiviral activity of these novel phosphoramidate nucleosides was partially explained by the increased intracellular formation of the adenosine dioxolane triphosphate.