A Short, Flexible Route toward 2‘-<i>C</i>-Branched Ribonucleosides

Harry-O’kuru, Rogers E.; Smith, and Jennifer M.; Wolfe, Michael S.

doi:10.1021/jo961893+

Cited by 64 publications

(51 citation statements)

References 34 publications

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“…Nucleoside analogs 2 to 4 were prepared as described in the literature (9,12), and the synthesis of compounds 11 to 14 is summarized in schemes 1 to 3 in the supplemental material. Dess-Martin oxidation of ␣-D-1,3,5-tri-O-benzoyl-ribofuranose (compound 5) followed by reaction of the ketone compound 6 with ethynylmagnesium bromide or 1-propynyl magnesium bromide afforded the desired modifi- cation of ribose.…”

Section: Chemistrymentioning

confidence: 99%

“…Further benzoylation of the tertiary alcohol gave the intermediate compounds 7 and 8, respectively (scheme 1 in the supplemental material). The bases were then introduced using Vorbruggen methodology followed by aminolysis, providing access to nucleoside analogs 11 to 13 (9,12). Reaction of 6-chloro-9H-purin-2-ylamine with compound 7 and hydrolysis of the resulting chloro intermediate with NaOH led to compound 14 (schemes 2 and 3 in the supplemental material).…”

Section: Chemistrymentioning

confidence: 99%

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Inhibition of Dengue Virus RNA Synthesis by an Adenosine Nucleoside

Chen

Yin

Duraiswamy

et al. 2010

Antimicrob Agents Chemother

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We recently reported that (2R,3R,4R,5R)-2-(4-amino-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydro-furan-3,4-diol is a potent inhibitor of dengue virus (DENV), with 50% effective concentration (EC 50 ) and cytotoxic concentration (CC 50 ) values of 0.7 M and >100 M, respectively. Here we describe the synthesis, structure-activity relationship, and antiviral characterization of the inhibitor. In an AG129 mouse model, a single-dose treatment of DENV-infected mice with the compound suppressed peak viremia and completely prevented death. Mode-of-action analysis using a DENV replicon indicated that the compound blocks viral RNA synthesis. Recombinant adenosine kinase could convert the compound to a monophosphate form. Suppression of host adenosine kinase, using a specific inhibitor (iodotubercidin) or small interfering RNA (siRNA), abolished or reduced the compound's antiviral activity in cell culture. Studies of rats showed that 14 C-labeled compound was converted to mono-, di-, and triphosphate metabolites in vivo. Collectively, the results suggest that this adenosine inhibitor is phosphorylated to an active (triphosphate) form which functions as a chain terminator for viral RNA synthesis.The family Flaviviridae consists of three genera, Flavivirus, Pestivirus, and Hepacivirus. Many viruses from the genus Flavivirus are arthropod-borne and cause significant human diseases. The four serotypes of dengue virus (DENV) alone pose a health threat to 2.5 billion people worldwide, leading to 50 to 100 million human infections and 500,000 cases of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) each year (11). Besides DENV, other flaviviruses, such as West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), and tick-borne encephalitis virus (TBEV), also cause frequent outbreaks throughout the world. No clinically approved antiviral therapy is currently available for treatment of flavivirus infections. Human vaccines are available only for YFV, JEV, and TBEV. The development of a successful DENV vaccine has been challenging due to the facts that (i) the vaccine should simultaneously induce a long-lasting protection against all four DENV serotypes and (ii) an incompletely immunized individual may be sensitized to the lifethreatening DHF or DSS. The challenge associated with the development of a vaccine underlines the importance of antiviral development for DENV and other flaviviruses.The flavivirus genome is a single-strand RNA of plus-sense polarity. The single open reading frame from the 11-kb viral genome encodes three structural proteins (capsid [C], premembrane [prM], and envelope [E]) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Nonstructural proteins are responsible for viral replication. Of those, NS3 and NS5 have enzymatic activities. The N-terminal domain of NS3 (with NS2B as a cofactor) functions as a serine protease, and the C-terminal domain acts as an RNA helicase, an RNA triphosphatase, and an NTPase (10,34,35). The N-...

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Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Inhibition of Dengue Virus RNA Synthesis by an Adenosine Nucleoside

Chen

Yin

Duraiswamy

et al. 2010

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…This precursor sugar is easily accessible from commercially available material, and 2′-C-methyl-uridine (4) was prepared as described in the literature (Harry-O'kuru et al, 1997b;Tang et al, 1999), introducing only a slight modification that permitted easy isolation. For practical considerations, we prepared the cytosine derivative (5) converting the uracil nucleoside (Figure 1) via the transient generation of the 4-nitrophenoxy-derivative (Legorburu et al, 1999).…”

Section: Chemistrymentioning

confidence: 99%

2′-C-Methyl Branched Pyrimidine Ribonucleoside Analogues: Potent Inhibitors of RNA Virus Replication

Benzaria

Bardiot

Bouisset

et al. 2007

Antivir Chem Chemother

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“…Starting from 2′-C-methyl adenosine (13), 24 compound 14 was obtained via a silylation, benzoylation, and desilylation sequence. The same chemistry described in Scheme 2 was applied to 14 to make phosphonate 5 and its diphosphate derivative 5a.…”

Section: Synthesis Of Adenosine Phosphonate Analoguesmentioning

confidence: 99%

Design, Synthesis, and Antiviral Activity of Adenosine 5‘-Phosphonate Analogues as Chain Terminators against Hepatitis C Virus

Koh

Shim

et al. 2005

J. Med. Chem.

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A series of adenosine 5′-phosphonate analogues were designed to mimic naturally occurring adenosine monophosphate. These compounds (1-5) were synthesized and evaluated in a cellular hepatitis C virus (HCV) replication assay. To improve cellular permeability and enhance the anti-HCV activity of these phosphonates, a bis(S-acyl-2-thioethyl) prodrug for compound 5 was prepared, and its cellular activity was determined. To elucidate the mechanism of action of these novel adenosine phosphonates, their diphosphate derivatives (1a-5a) were synthesized. Further nucleotide incorporation assays by HCV NS5B RNA-dependent RNA polymerase revealed that 2a and 3a can serve as chain terminators, whereas compounds 1a, 4a, and 5a are competitive inhibitors with ATP. Additional steady-state kinetic analysis determined the incorporation efficiency of 2a and 3a as well as the inhibition constants for 1a, 4a, and 5a. The structure-activity relationships among these compounds were analyzed, and the implication for nucleoside phosphonate drug design was discussed.

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A Short, Flexible Route toward 2‘-C-Branched Ribonucleosides

Cited by 64 publications

References 34 publications

Inhibition of Dengue Virus RNA Synthesis by an Adenosine Nucleoside

Inhibition of Dengue Virus RNA Synthesis by an Adenosine Nucleoside

2′-C-Methyl Branched Pyrimidine Ribonucleoside Analogues: Potent Inhibitors of RNA Virus Replication

Design, Synthesis, and Antiviral Activity of Adenosine 5‘-Phosphonate Analogues as Chain Terminators against Hepatitis C Virus

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