Bicyclic nucleoside inhibitors of Varicella–Zoster virus: The effect of branching in the p-alkylphenyl side chain

Luoni, G; McGuigan, Christopher; Andrei, Gracíela; Snoeck, Robert; Clercq, Erik De; Balzarini, Jan

doi:10.1016/j.bmcl.2005.05.071

Cited by 21 publications

(11 citation statements)

References 7 publications

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“…This is an important insight into the structure-brain uptake relationship of this class of compounds as the p-pentylphenyl derivative is currently in the drug development phase for use in shingles infection. 28 Our experience with radiolabeled BCNAs suggests that a potential BCNA tracer for in vivo visualization of VZV-tk should have good affinity for the enzyme VZV-TK (IC 50 value ideally be o5 mM) and should have reasonable lipophilicity (log P value ideally be over 1) for a good accumulation in VZV-tk expressing cells.…”

Section: Resultsmentioning

confidence: 98%

Synthesis and biological evaluation of carbon‐11‐labeled acyclic and furo[2,3‐d]pyrimidine derivatives of bicyclic nucleoside analogues (BCNAs) for structure–brain uptake relationship study of BCNA tracers

Chitneni

Balzarini

Celen

et al. 2008

Labelled Comp Radiopharmac

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We reported earlier on radiolabeled alkoxyphenyl bicyclic nucleoside analogues (BCNAs) as potential positron emission tomography (PET) reporter probes for imaging of varicella zoster virus thymidine kinase (VZV-tk) gene in vivo. Despite their favorable physicochemical properties, these tracers are not taken up in the brain in mice. In order to probe the role of the deoxyribose sugar moiety in blood-brain barrier (BBB) penetration of these molecules, we have synthesized and evaluated a carbon-11-labeled acyclic bicyclic nucleoside derivative (

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Section: Resultsmentioning

confidence: 98%

Synthesis and biological evaluation of carbon‐11‐labeled acyclic and furo[2,3‐d]pyrimidine derivatives of bicyclic nucleoside analogues (BCNAs) for structure–brain uptake relationship study of BCNA tracers

Chitneni

Balzarini

Celen

et al. 2008

Labelled Comp Radiopharmac

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“…Not only were these analogues extremely potent against VZV, they also demonstrated low cytotoxicity at levels up to 50 µM (Balzarini and McGuigan, 2002; McGuigan et al, 1999). As with the C5 alkyl study, increased branching of the BCNAs was associated with a decrease in antiviral activity, with the optimum length proving to be C8-C10 (McGuigan et al, 1999; Luoni et al, 2005).…”

Section: Modifications To the Nucleobasementioning

confidence: 85%

The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold

2018

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This is the first of two invited articles reviewing the development of nucleoside-analogue antiviral drugs, written for a target audience of virologists and other non-chemists, as well as chemists who may not be familiar with the field. Rather than providing a simple chronological account, we have examined and attempted to explain the thought processes, advances in synthetic chemistry and lessons learned from antiviral testing that led to a few molecules being moved forward to eventual approval for human therapies, while others were discarded. The present paper focuses on early, relatively simplistic changes made to the nucleoside scaffold, beginning with modifications of the nucleoside sugars of Ara-C and other arabinose-derived nucleoside analogues in the 1960's. A future paper will review more recent developments, focusing especially on more complex modifications, particularly those involving multiple changes to the nucleoside scaffold. We hope that these articles will help virologists and others outside the field of medicinal chemistry to understand why certain drugs were successfully developed, while the majority of candidate compounds encountered barriers due to low-yielding synthetic routes, toxicity or other problems that led to their abandonment.

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“…11 Starting from the 6-p-alkylphenyl pharmacophore several new furo[2,3-d]pyrimidine nucleoside analogues were recently synthesized: the effect of branching in the p-alkylphenyl side chain ( Fig. 5) proved detrimental to antiviral activity; 13 conversion of the 2-deoxyribose to 2,3-dideoxyribose ( Fig. 6) in the p-alkylphenyl substituted compounds reduced the antiviral activity by 1000-fold, down to the level observed for acyclovir.…”

Section: S T R U C T U R E -A C T I V I T Y R E L a T I O N S H I Pmentioning

confidence: 99%

Highly potent and selective inhibition of varicella‐zoster virus replication by bicyclic furo[2,3‐d]pyrimidine nucleoside analogues

Clercq

2003

Medicinal Research Reviews

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The bicyclic furo[2,3-d]pyrimidine nucleoside analogues represent an entirely new class of fused furopyrimidine derivatives with unprecedented selectivity for varicella-zoster virus (VZV). From extensive structure-activity relationship (SAR) studies, the 6-(p-alkylphenyl)substituted furopyrimidine derivatives Cf 1742 and Cf 1743 emerged as the most potent inhibitors of VZV replication: they were found to inhibit both laboratory VZV strains and clinical VZV isolates at subnanomolar concentrations, while not being toxic to the host cells at 100,000-fold higher concentrations. Although the precise mechanism of action of these compounds remains to be elucidated, it is clear that for their antiviral activity they depend on phosphorylation by the VZV-encoded thymidine kinase. The furo[2,3-d]pyrimidine nucleoside analogues are not susceptible to degradation by human or bacterial thymidine phosphorylase, which may otherwise release the free aglycone. Also, the latter is not inhibitory to dihydropyrimidine dehydrogenase, an enzyme involved in the degradation of thymine, uracil, and the anticancer agent 5-fluorouracil. Further development of the furo[2,3-d]pyrimidine nucleoside analogues as new therapeutic modalities for the treatment of VZV infections (i.e., varicella and herpes zoster) seems highly justified.

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Bicyclic nucleoside inhibitors of Varicella–Zoster virus: The effect of branching in the p-alkylphenyl side chain

Cited by 21 publications

References 7 publications

Synthesis and biological evaluation of carbon‐11‐labeled acyclic and furo[2,3‐d]pyrimidine derivatives of bicyclic nucleoside analogues (BCNAs) for structure–brain uptake relationship study of BCNA tracers

Synthesis and biological evaluation of carbon‐11‐labeled acyclic and furo[2,3‐d]pyrimidine derivatives of bicyclic nucleoside analogues (BCNAs) for structure–brain uptake relationship study of BCNA tracers

The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold

Highly potent and selective inhibition of varicella‐zoster virus replication by bicyclic furo[2,3‐d]pyrimidine nucleoside analogues

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