Synthesis and Anti-HCV Activity of 3',5'-cyclic SATE Phosphonodiester Nucleoside as a Novel Prodrug

Abstract

A novel 2',4'-dimethyl carbocyclic adenosine 5'-phosphonic acid analogue (20) was prepared using acyclic stereoselective route from commercially available 4-hydroxybutan-2-one (4). To improve cellular permeability and enhance the anti-HCV activity of this phosphonic acid, a 3',5'-cyclic SATE phosphonodiester nucleoside prodrug (22) was prepared. The synthesized phosphonic nucleoside analogues, (20) and (22), were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line.

Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase

“…Another application of a 3′,5′-cyclic-SATE ester prodrug of 2′- C -methyladenosine entailed the application to a 4′-substituted carbocyclic nucleoside 68 and employed a phosphonate that would ultimately produce a stable form of the nucleoside 5′-monophosphate (Figure ) . The resulting 2′- C -methyladenosine 3′,5′-cyclic phosphonate SATE prodrug 69 (EC 50 = 27.6 μM) was only modestly active in the HCV replicon assay, was <3-fold more potent than the phosphonate product it was intended to deliver, and was >14-fold less active than 2′- C -methyadenosine 8 .…”