Synthesis of the 5-phosphono-pent-2-en-1-yl nucleosides: A new class of antiviral acyclic nucleoside phosphonates

Choo, Hyunah; Beadle, James R.; Chong, Youhoon; Trahan, Julissa; Hostetler, Karl Y.

doi:10.1016/j.bmc.2006.11.038

Cited by 22 publications

(11 citation statements)

References 23 publications

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“…Choo et al reported the preparation of the alkoxyalkyl cis- 5-phosphono-pent-2-en-1-yl nucleoside prodrug 299 . 123 Uracil diethyl phosphonate derivative 297 was first synthesized by Mitsunobu coupling between N 3 -benzoylated uracil and ( Z )-diethyl (5-hydroxypent-3-en-1-yl)phosphonate followed by debenzoylation with ammonia in methanol. Triisopropylphenylsulfonylation and subsequent aminolysis converted the uracil diethylphosphonate 297 into its corresponding cytosine derivative 298 in 75% yield.…”

Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

et al. 2014

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Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

et al. 2014

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“…A new class of acyclic nucleoside phosphonate was recently reported having a 5-phosphono-pent-2-en-1-yl acyclic side chain loosely based on the structure of d4T (Choo et al 2007a). Unmodified acyclic nucleoside phosphonates of this class are inactive against HSV-1.…”

Section: Application Of the Same Strategy To Other Acyclic Nucleosmentioning

confidence: 99%

“…Unmodified acyclic nucleoside phosphonates of this class are inactive against HSV-1. However, when esterified with HDP, the HDP-PPen-T compound exhibits antiviral activity against HSV-1 in vitro (Choo et al, 2007a). None of the unmodified PPen nucleosides are active against HIV or HBV (Choo et al, 2007b).…”

Section: Application Of the Same Strategy To Other Acyclic Nucleosmentioning

confidence: 99%

“…All types of acyclic nucleoside phosphonates show enhancement of antiviral activity, presumably due to increased cellular penetration of the alkoxyalkyl esterified compounds and increased metabolic conversion to their diphosphates (triphosphate equivalents) (Aldern et al 2003, Magee et al 2008). In a number of instances, acyclic nucleoside phosphonates which were reported to be inactive showed antiviral activity as their HDP esters (Hostetler et al, 2006, Choo et al, 2007a, Choo et al, 2007b, Prichard et al, 2008). This emphasizes the probability that earlier in vitro antiviral screening with unmodified acyclic nucleoside phosphonates in virus-infected cells has systematically underestimated the antiviral activity of most members of this class.…”

Section: Application Of the Same Strategy To Other Acyclic Nucleosmentioning

confidence: 99%

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Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: Current state of the art

2009

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Although the acyclic nucleoside phosphonates cidofovir, adefovir and tenofovir are approved for treating human cytomegalovirus, hepatitis B and HIV infections, respectively, their utility is limited by low oral bioavailability, renal toxicity and poor cell penetration. Research over the past decade has shown that these undesirable features can be eliminated by esterifying the compounds with an alkoxyalkyl group, in effect disguising them as lysophospholipids. In this modified form, the drugs are readily taken up in the gastrointestinal tract and have a prolonged circulation time in plasma. The active metabolite also has a long half life within cells, permitting infrequent dosing. Because these modified drugs are not recognized by the transport mechanisms that cause the accumulation of acyclic nucleoside phosphonates in renal tubular cells, they lack nephrotoxicity. Alkoxyalkyl esterification also markedly increases the in vitro antiviral activity of acyclic nucleoside phosphonates by improving their delivery into cells. For example, an alkoxyalkyl ester of cyclic-cidofovir, a less soluble compound, retains antiviral activity for 3 months following a single intravitreal injection. Two of these novel compounds, hexadecyloxypropyl-cidofovir (CMX-001) and hexadecyloxypropyl-tenofovir (CMX-157) are now in clinical development. This article focuses on the hexadecyloxypropyl and octadecyloxyethyl esters of cidofovir and (S)-HPMPA, describing their synthesis and the evaluation of their in vitro and in vivo activity against a range of orthopoxviruses, herpesviruses, adenoviruses and other double-stranded DNA viruses. The extension to other nucleoside phosphonate antivirals is highlighted, demonstrating that this novel approach can markedly improve the medicinal properties of these drugs.

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“…HSV-1 is responsible for the lesions at orofacial sites that are commonly known as cold sores. HSV-2 is responsible for mucocutaneous genital infections [3]. Much research has been focused on HSV-1 and HSV-2 as these viruses have a high incidence rate (1.6 million new cases of HSV-2 predicted per year in the United States) and prevalence [50-95% (HSV-1) and 6-50% (HSV-2)] [4].…”

Section: Introductionmentioning

confidence: 99%