2'-Spirocyclopropyl-carbocyclic Nucleoside as a Novel Scaffold for Potent Anti-HCV Agents

Abstract

The discovery of 2'-spirocyclopropyl-ribocytidine (J. Med. Chem. 2010, 53, 8150-8160) as a potent inhibitor of RNA synthesis by NS5B (IC 50 = 7.3 µM), the RNA polymerase encoded by hepatitis C Virus (HCV), has led to the synthesis and biological evaluation of several carbocyclic versions of 2'-spiropropyl-nucleosides. The cyclopentenol intermediate 7 was successfully constructed via ring-closing metathesis (RCM) from divinyl 6. Spirocyclopropanation of enone 8 was effected by using (2-chloroethyl)-dimethylsulfonium iodide and potassium tert-butoxide to form the desired intermediate 9. The synthesized nucleoside analogues 21-24 were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line. Among them, the cytosine nucleoside analogue 22 exhibited significant anti-HCV activity (EC 50 = 18.2 µM).

Advances in the Synthesis of Spirocyclic Nucleosides

“…This has led to the synthesis of different classes of spirocyclic nucleosides, such as C-1′-spiro-, [30][31][32][33] C-2′-spiro-, [34][35][36][37] C-3′-spiro-, 38,39 and C-4′-spirocyclic nucleosides [40][41][42] (Figure 3), and some of these have demonstrated excellent biological activities. The majority of spirocyclic nucleoside synthetic methods focus on utilizing carbohydrate derivatives to produce the appropriate stereochemistry in the sugar ring.…”

“…Hong and co-workers synthesized 4′-methylated 2′-spirocarbocyclic nucleoside analogues 175a-d and 176a-d via nucleobase coupling to rel-(4S,6S,7S)-7-(tert-butyldimethylsiloxy)-6-(tert-butyldimethylsiloxymethyl)-6-methylspiro [2.4]heptan-4-yl methanesulfonate 174 followed by desilylation. 36 The C-1 mesylated compound 174 was synthesized from enone 167, which in turn was synthesized from an acetol. The key scaffold, spirocyclopropyl group was introduced in enone 167 by using (2-chloroethyl)dimethylsulfonium iodide to afford nucleoside 168 (Scheme 23).…”