title: 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 potencyversusHIV-1 when compared to their corresponding parent nucleoside and were up to 300-fold more potentversusHBV. No cytotoxicity was observed up to 100 μM in the various cell systems tested, except for compound17and18which displayed a CC50of 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.
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, Georgia 30033, USA.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Bondada
authors.forename: Mervi
authors.initials: M
authors.lastname: Detorio
authors.forename: Leda
authors.initials: L
authors.lastname: Bassit
authors.forename: Sijia
authors.initials: S
authors.lastname: Tao
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Montero
authors.forename: Tyana M
authors.initials: TM
authors.lastname: Singletary
authors.forename: Hongwang
authors.initials: H
authors.lastname: Zhang
authors.forename: Longhu
authors.initials: L
authors.lastname: Zhou
authors.forename: Jong-Hyun
authors.initials: JH
authors.lastname: Cho
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Coats
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
keywords: Dioxolane adenosine nucleoside; HBV; HIV; ProTide; nucleoside reverse transcriptase inhibitor; phosphoramidate prodrug