Synthesis and anti-HIV activity of some haloalkyl phosphoramidate derivatives of 3′-azido-3′-deoxythymidine (AZT): potent activity of the trichloroethyl methoxyalaninyl compound

McGuigan, Christopher; Devine, Kevin G.; O'Connor, Timothy J.; Kinchington, D.

doi:10.1016/0166-3542(91)90071-x

Cited by 60 publications

(31 citation statements)

References 16 publications

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“…Since first described in early 1990s (24)(25)(26)(27)(28), amidate prodrugs of nucleotides have been the most successfully explored class of prodrugs to bypass the first phosphorylation step of nucleosides or to deliver nucleoside phosphonates into cells (29). TAF is the first nucleotide phosphonoamidate prodrug to successfully complete a proof-of-concept clinical efficacy study (30).…”

Section: Discussionmentioning

confidence: 99%

Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors

Birkuš

Bam

Willkom

et al. 2016

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 99%

Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors

Birkuš

Bam

Willkom

et al. 2016

Antimicrob Agents Chemother

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“…181 ppm) in the region expected for an alkyl phosphorodichloridite (Mark et aI., 1969). This material reacted cleanly with AZT in THF containing N-methyl imidazole; conditions that we have found most successful for the reaction of amino phosphorochloridates with nucleosides (McGuigan et a/., 1991). The presumed intermediate nucleoside alkyl phosphorochloridite was hydrolysed in situ to give the target compound (3a, Fig.…”

Section: Mementioning

confidence: 99%

“…The free 5'-monophosphate of AZT is of limited therapeutic interest on account of the poor membrane penetration by (charged) nucleotides (Cohen and Plunkett, 1975). Thus, much effort has gone into studies of masked nucleotides in an attempt to improve the therapeutic properties of the parent nucleoside analogues (Freed et al, 1989;Devine et al, 1990;McGuigan et al, 1990a;McGuigan et al, 1990b;McGuigan et al, 1990c;Henin et al, 1991;McGuigan et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Alkyl Hydrogen Phosphonate Derivatives of the anti-HIV Agent AZT may be Less Toxic than the Parent Nucleoside Analogue

McGuigan

Bellevergue

Jones

et al. 1994

Antivir Chem Chemother

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SummaryNovel alkyl hydrogen phosphonate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridite chemistry. These materials are designed to act as labile membrane-soluble prodrugs of the bioactive free nucleotides. In vitro evaluation has revealed the compounds to have a pronounced and selective antiviral action. Shortchain (C1-C7) alkyl derivatives are more potent than the parent hydrogen phosphonate, whilst one longchain (C18) compound is less active. In an assay that demonstrates the toxicity of the parent drug AZT, the alkyl H-phosphonates appear to be less cytotoxic, whilst retaining full antiviral activity. Lastly, the compounds are all poorly active in a cell llne (JM) that is poorly responsive to AZT, indicating that they act as depot forms of the nucleoside rather than of the free nucleotide.

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“…Given our experience in the improvement of the therapeutic performance of bio-active nucleosides by suitable phosphate modification [8,9,10,11,12] we wondered if a similar strategy might lead to enhancement of the properties of the parent ALP. *Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of substituted phosphate triester alkyl lyso phospholipids (ALPs) as novel potential anti‐neoplastic agents

McGuigan

Wang

Riley³

1995

FEBS Letters

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Phosphate triester derivatives of the anti-neoplastic alkyi iyso phospholipid (ALP) have been prepared as novel potential therapeutic agents. In particular, symmetrical phosphate triesters have been prepared, using phosphorochloridate chemistry. The compounds have been fully characterised by a range of techniques, and assayed for their inhibition of DNA synthesis by mammalian cells in culture. The compounds are generally inhibitory towards DNA synthesis in the pM range. However, the magnitude of the effect varies greatly with the phosphate structure; alkynyl and glycol substituted phosphates being especially potent.In a recent paper [13] we described our initial results regarding the synthesis of some novel ALPs, modified in the phosphate region. It was a notable and surprising observation that simple dialkyl blocked phosphate derivatives are active in vitro and that simple structure activity trends appear to operate. In this paper we describe the synthesis of some novel ALPs, further modified in the phosphate region in the hope of improving activity at lower concentration, and we discuss their evaluation in vitro. In particular we study the effect on anti-cancer activity of substitution within the alkyl-phosphate region.

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Synthesis and anti-HIV activity of some haloalkyl phosphoramidate derivatives of 3′-azido-3′-deoxythymidine (AZT): potent activity of the trichloroethyl methoxyalaninyl compound

Cited by 60 publications

References 16 publications

Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors

Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors

Alkyl Hydrogen Phosphonate Derivatives of the anti-HIV Agent AZT may be Less Toxic than the Parent Nucleoside Analogue

Synthesis and biological evaluation of substituted phosphate triester alkyl lyso phospholipids (ALPs) as novel potential anti‐neoplastic agents

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