Bioorganic & Medicinal Chemistry Letters
Synthesis and evaluation of Janus type nucleosides as potential HCV
NS5B polymerase inhibitors
Longhu Zhou a, Franck Amblard a, Hongwang Zhang a, Tamara R. McBrayer b, Mervi A. Detorio a,
Tony Whitaker b, Steven J. Coats b, Raymond F. Schinazi a,
⇑
a Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur,
GA 30033, USA
b RFSPharma, LLC, 1860 Montreal Road, Tucker, GA 30084, USA
a r t i c l e i n f o
a b s t r a c t
The synthesis of new ribo and 20-b-C-methyl ribo Janus type nucleosides J-AA, J-AG and J-AU is reported
along with their ability to block HCV and HIV replication. Their toxicity was also assessed in Huh7, human
lymphocytes, CEM and Vero cells.
Article history:
Received 18 February 2013
Revised 14 March 2013
Accepted 20 March 2013
Available online 29 March 2013
Published by Elsevier Ltd.
Keywords:
HCV
Antiviral
Prodrug
Janus
Hepatitis C virus (HCV), an enveloped single-stranded positive
sense enveloped RNA virus discovered in 1989,1 is a leading cause
of long term liver cirrhosis, resulting in liver transplantation, liver
failure and hepatocellular carcinoma.2 Globally, there are an esti-
mated 170 million persons infected with the virus and 3–4 million
persons are newly infected each year. Despite the existence of
(Fig. 2), presenting one face with a Watson–Crick donor/acceptor ar-
ray of a guanine and the other face with an array of an adenine, could
in principle, by rotation of the glycosidic bond, pair with either a
cytosine or a uracil. Thus, we report herein the synthesis and the bio-
logical evaluation of ribo and new 20-b-C-methyl ribo Janus type
nucleosides J-AA, J-AG and J-AU (Fig. 2; R = H or Me).
treatments involving pegylated interferon-
a
(IFN) and ribavirin
The Janus type nucleosides 12a, 14a and 19a were previously
reported by Townsend,9 we have included our resynthesis of these
nucleosides for comparison to the synthesis of the 20-b-C-methyl
ribo series and also to evaluate and compare both series for antivi-
ral and cytotoxic activity. The synthesis of Janus type nucleosides
12a–b (J-AU) is summarized in Scheme 1. The Vorbrüggen coupling
reaction between 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimi-
(RBV), with or without protease inhibitors (PI) boceprevir (Victrel-
is) and telaprevir (Incivek),3 the limited efficacy and side effects of
current therapies emphasize the need for additional improved
therapeutic agents. Nucleoside inhibitors that target HCV NS5B
polymerase have demonstrated clinical advantages of broader
activity against various HCV genotypes and a higher barrier to
the development of resistant viruses when compared to all other
classes of HCV inhibitors.4 To date a number of 20-modified nucleo-
sides have shown potent activity against HCV (Fig. 1).5,6 IDX-184 1,
RO-5024048/RG-7128 2, and PSI-7977 (GS-7977) 3 are in advanced
clinical trials as effective anti-HCV agents. Interestingly, highly
base-modified tricyclic derivatives such as 47 and 58 have also
shown potent anti-HCV activity.
dine 611and 1-O-acetyl-2,3,5-tri-O-benzoyl-b-
20-b-C-methyl-1,2-di-O-benzoyl-3,5-di-O-toluyl-b-
D-ribofuranose 7a or
D
-ribofuranose
7b12using N,O-bis(trimethylsilyl)acetamide (BSA) as the silylation
agent and TMSOTf as the Lewis acid provided compounds 8a and
8b in 71% and 65%, respectively.13 Compounds 8a–b were then
deprotected in saturated methanolic ammonia to give 9a–b. Subse-
quent halogen displacement with liquid ammonia in a steel bomb
was followed by treatment with hydroxylamine14 in ethanol which
afforded compounds 11a–b in good yields. Finally, J-AU derivatives
12a–b15 were obtained in 51% and 46% yield, respectively, by treat-
ment of amides 11a–b with diethyl carbonate in presence of so-
dium ethoxide. It is noteworthy that 1H NMR spectral data for
Janus base nucleosides denote the presence of only one isomer
(for compound 12b, 20Me signal appears as a singlet), clearly indi-
cating free rotation of the base.
Based on these compounds and inspired by Townsend’s work on
linear tricyclicnucleosides,9 we prepared a seriesof new nucleosides
with potential anti-HCV activity that may be viewed as possessing
the feature of two completely different bases simultaneously
(Fig. 2). These dual bases or Janus type10 nucleosides, such as J-GA
⇑
Corresponding author.
0960-894X/$ - see front matter Published by Elsevier Ltd.