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-(2R,4R)-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 versus HIV-1 when compared to their corresponding parent nucleoside and were up to 300-fold more potent versus HBV. No cytotoxicity was observed up to 100 μM in the various cell systems tested, except for compound 17 and 18 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.

The Current Status of O‐Heterocycles: A Synthetic and Medicinal Overview

“…Furthermore, ar adioligand-binding assay revealed 39 (Figure 9) as the most interesting compound of the series, displaying high affinity and selectivity for the sigma receptor.A dditionally, 39 exerteda nti-opioid effects on both kappa and mu receptormediated analgesia, suggesting agonist behaviour at the sigma receptor. [96] The authors reported the synthesis of an umber of 2-{N-[2-(5,5-dimethyl-1,3-dioxane-2-yl)ethyl]aminoacyl}amino-2-deoxy-d-glucopyranosides from glucosamine, 2,2-dimethyl-1,3-propanediol and 1,1,3,3-tetramethoxypropane, and further evaluated their anti-inflammatory potential.…”

“…Whereas the 6methoxy and 6-cyclopropylaminop urine modifications resulted in as ignificantl oss of activity,t heir corresponding phosphoramidates possessed 3600-fold greater potency against HIV-1 and up to 300-fold greater potency against HBV.C ompound 41 (Figure 9) wast he found to be most interesting compound with no observed cytotoxicity and potent sub-micromolar anti-HIVand anti-HBV activity. [96]…”

Nucleosides and Nucleotides for the Treatment of Viral Diseases

“…Adenosine deaminase converts amdoxovir, via hydrolysis of the C-6 amino group, to DXG, which is then converted to the triphosphate active metabolite. 21 The most potent and least cytotoxic analog was 26 (EC 50 ¼ 0.086 μM). Amdoxovir administered to HIV-1-infected patients at 500 mg bid for 10 days resulted in a À1.00 log 10 reduction in viral load, and a À2.00 log 10 viral load reduction was observed in combination with zidovudine (200 mg bid).…”

The diverse pharmacology and medicinal chemistry of phosphoramidates – a review

“…35 Some reports have demonstrated that phosphoramidate derivatives of dioxolane sugar nucleosides (DOA) possessing pyrimidines improved the antiviral potency in vitro. 42,43 The phosphoramidates 38 and 39, synthesized by Bondada et al 44 had evaluated their activities against HIV-1 and HBV. The compound 38 displayed up to a 1070-fold greater potency versus HIV-1 compared to their corresponding parent nucleoside (40), and, notably, were up to 12-fold more potent versus HBV (Fig.…”