6-Hydrazinopurine 2′-methyl ribonucleosides and their 5′-monophosphate prodrugs as potent hepatitis C virus inhibitors

Gunić, Esmir; Chow, Suetying; Rong, Frank; Ramasamy, Kanda S.; Raney, Anneke K.; Li, David Yunzhi; Huang, Jingfan; Hamatake, Robert; Hong, Zhi; Girardet, Jean‐Luc

doi:10.1016/j.bmcl.2007.02.029

Cited by 24 publications

(14 citation statements)

References 7 publications

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“…Recently, modified bases of JA23 and JA27 were shown to inhibit hepatitis C virus replication when attached to a 2Ј-Cmethyl ribose (14,15). However, those compounds were found not to function as substrates for adenosine kinase, with administration of a cyclic monophosphate prodrug increasing efficacy significantly.…”

Section: Discussionmentioning

confidence: 99%

Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues

Graci¹,

Too

Smidansky³

et al. 2008

Antimicrob Agents Chemother

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RNA viruses exhibit extraordinarily high mutation rates during genome replication. Nonnatural ribonucleosides that can increase the mutation rate of RNA viruses by acting as ambiguous substrates during replication have been explored as antiviral agents acting through lethal mutagenesis. We have synthesized novel N-6-substituted purine analogues with ambiguous incorporation characteristics due to tautomerization of the nucleobase. The most potent of these analogues reduced the titer of poliovirus (PV) and coxsackievirus (CVB3) over 1,000-fold during a single passage in HeLa cell culture, with an increase in transition mutation frequency up to 65-fold. Kinetic analysis of incorporation by the PV polymerase indicated that these analogues were templated ambiguously with increased efficiency compared to the known mutagenic nucleoside ribavirin. Notably, these nucleosides were not efficient substrates for cellular ribonucleotide reductase in vitro, suggesting that conversion to the deoxyriboucleoside may be hindered, potentially limiting genetic damage to the host cell. Furthermore, a high-fidelity PV variant (G64S) displayed resistance to the antiviral effect and mutagenic potential of these analogues. These purine nucleoside analogues represent promising lead compounds in the development of clinically useful antiviral therapies based on the strategy of lethal mutagenesis.Natural nucleotides exist as tautomers in solution, and tautomerization of the nucleobases in DNA has been recognized as a likely mutagenic mechanism ever since the double-helical structure of the DNA molecule was first deduced by Watson and Crick (33,36). The keto (for G and U) and amino (for A and C) tautomers of the natural nucleotides are the predominant species with tautomeric constants (K T ) on the order of 10 5 . However, tautomeric conversion to the rare enol or imino forms of the nucleobases can lead to altered hydrogen bonding specificity and thus mutagenesis through noncanonical basepairing interactions. This has become known as the "rare tautomer" hypothesis of mutation (19,29).The tautomerization of bases to yield ambiguous base-pairing properties has also been exploited in the design of novel nucleoside drugs, including 5-hydroxy-2Ј-deoxycytidine (22) and 5-aza-5,6-dihydro-2Ј-deoxycytidine (KP-1212) (18, 25) (Fig. 1A). However, attempts to design clinically useful antiviral compounds around this premise have met with only limited success (13,16,18,25).Nucleobases exhibiting multiple conformations due to rotation or tautomerization have received attention as potential antiviral agents acting through lethal mutagenesis (11,22). Since the discovery that ribavirin (Fig. 1B) can act as a lethal mutagen (7), likely through rotation of the exocyclic carboxamide moiety, the concept of lethal mutagenesis as an antiviral strategy has received considerable attention (5,11,12).Recently, we have demonstrated that the ribonucleoside analogue rP (Fig. 1C) can act as a potent mutagen of poliovirus (PV) in vitro (13). Tautomerization of the nucleobas...

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Section: Discussionmentioning

confidence: 99%

Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues

Graci¹,

Too

Smidansky³

et al. 2008

Antimicrob Agents Chemother

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“…This method has been successfully applied to the synthesis of various derivatives of AZT ( 101 ), 23 adenallene ( 102 ), 53 9-(2′-β- C -methyl-β- d -ribofuranosyl) substituted purines ( 103 , 104 ), 54,55 pyrrolopyrimidine nucleoside ( 105 ), 56 and IsoddA ( 106 ) (Scheme 31). 57 …”

Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%

“…Activities of these (SATE)-cMP prodrugs have been shown to be similar to regular 5′-bis(SATE)-MP prodrugs of nucleosides. 55 …”

Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

et al. 2014

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“…However, an increase in cytotoxicity was also observed with both prodrugs exhibiting CC 50 values ≤8.4 µM. Several SATE prodrugs of modified adenine derivatives (46, 48, 50 and 52-54; Figure 5) have also been synthesized by Gilead Sciences [54,55] and Valeant Pharmaceuticals International [48,56], and have been tested for anti-HCV activity. In all cases, the increased lipophilicity of the SATE prodrugs led to improved cell penetration capabilities and coincided with greater potent activity with EC 50 values as low as 0.02 µM for prodrug 52.…”

Section: S-acyl-2-thioethyl Prodrugsmentioning

confidence: 99%

“…In 2007, Valeant Pharmaceuticals International [48] reported that 6-hydrizinopurine-2′-C-methylnucleosides had poor stability and/or a poor selectivity index. This eventually led to the discovery of the corresponding ProTide prodrugs.…”

Section: Aryloxy Phosphoramidatementioning

confidence: 99%

Advances in nucleoside monophosphate prodrugs as anti-HCV agents

Bobeck¹,

Schinazi

Coats³

2010

Antiviral Therapy

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Nucleoside monophosphate prodrugs that are eventually bioconverted to the active nucleoside triphosphate (NTP) offer the potential to deliver increased intracellular NTP levels and/or organ-specific NTP enhancement. There are several classes of monophosphate prodrugs that have been applied to HCV drug discovery, and some of these approaches are currently being evaluated in humans. This review discusses recent advances in monophosphate prodrug approaches to improve oral absorption, stability and pharmacokinetic profile, including their advantages and potential pitfalls.

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6-Hydrazinopurine 2′-methyl ribonucleosides and their 5′-monophosphate prodrugs as potent hepatitis C virus inhibitors

Cited by 24 publications

References 7 publications

Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues

Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

Advances in nucleoside monophosphate prodrugs as anti-HCV agents

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