Aryl phosphate derivatives of AZT retain activity against HIV1 in cell lines which are resistant to the action of AZT

McGuigan, Christopher; Pathirana, Ranjith; Mahmood, Naheed; Devine, Kevin G.; Hay, Alan J.

doi:10.1016/0166-3542(92)90026-2

Cited by 159 publications

(138 citation statements)

References 16 publications

Supporting

Mentioning

131

Contrasting

Unclassified

Order By: Relevance

“…Moreover, this effect is retained in thymidine kinase-deficient cells, indicating a successful by-pass of this enzyme, and strongly supporting the suggested intracellular delivery of free nucleotides by this strategy. Whilst other researchers have recently reported the failure of the by-pass approach with phosphoramidates derived from ddu [13], we herein clearly demonstrate the success of this strategy with our previously reported aryloxy phosphoramidates [6] 2. Materials and methods…”

Section: Introductionsupporting

confidence: 60%

“…This compound was recently reported by another group, following our earlier phosphoramidate strategy [13]. However, we have found that aryloxy phosphoramidates are especially potent phosphate blocking groups for AZT, and appear to release the free nucleotides within cells, on the basis of data in thymidine kinase-deficient cells [6,20]. Thus, phenyl methoxyalaninyl phosphorochloridate was similarly prepared [20] and was allowed to react with ddU to give (3~) in good yield.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Certain phosphoramidate derivatives of dideoxy uridine (ddU) are active against HIV and successfully by‐pass thymidine kinase

et al. 1994

Self Cite

View full text Add to dashboard Cite

As part of our effort to deliver masked phosphates inside living cells we have discovered that certain phosphate triester derivatives of the inactive nucleoside analogue, dideoxy uridine (ddU) are inhibitors of HIV replication at PM levels. Moreover, we note that certain phosphoramidate derivatives retain their activity in thymidine kinase-deficient cells, which indicates that they do indeed act by intracellular release of the free nucleotide, and that they successfully by-pass the nucleoside kinase. The increased structural freedom in drug design which this allows may have implications for dealing with the emergence of resistance and may stimulate the discovery of improved therapeutic agents.

show abstract

Section: Introductionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Certain phosphoramidate derivatives of dideoxy uridine (ddU) are active against HIV and successfully by‐pass thymidine kinase

et al. 1994

Self Cite

View full text Add to dashboard Cite

show abstract

“…These compounds appear, instead, to act as sources of the free nucleoside, presumably via nucleoside-phosphate cleavage rather than aryl-phosphate cleavage. However, observation of the retention of activity in cells lacking thymidine kinase for certain phosphoramidate derivatives of AZT (McGuigan et al, 1992) was taken as strong support for a mechanism of action independent of thymidine kinase. The simplest explanation of this is intracellular release of free nucleotides.…”

Section: Introductionmentioning

confidence: 99%

“…1) reports have been produced on a variety of masked phosphate derivatives designed to act as membrane-soluble prodrugs of the bio-active phosphate forms (Freed et al, 1989;Farrow et el., 1990;McGuigan et al, 1990a,b,c;Henin et et., 1991;McGuigan et sl., 1991;McGuigan et et., 1992;Namane et el., 1992;Dessaux and Huynh-Dinh, 1993). It was noted that diaryl phosphates derived from AZT are potent inhibitors of viral replication in vitro, in Received 31 July, 1995;revised 1 September,1995;accepted 4 September, 1995.…”

Section: Introductionmentioning

confidence: 99%

Phosphoramidates as Potent Prodrugs of anti-HIV Nucleotides: Studies in the Amino Region

McGuigan

Cahard

Salgado

et al. 1996

Antivir Chem Chemother

View full text Add to dashboard Cite

SummaryNovel phosphoramidate derivatives of the anti-HIV nucleoside analogues AZT and d4T have been prepared by phosphorochloridate chemistry. These materials are designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotides. All compounds were fully characterised by a range of methods and were subjected to evaluation in vitro of their anti-HIV efficacy. A notable feature of the current study was that any attempt to replace the amino acid moiety of the phosphoramidate with a simple amine lead to a marked, virtually total loss of activity. Such simple phenyl alkylamino phosphate derivatives of either d4T or AZT inhibit HIV replication at cytotoxic concentrations and have no detectable antiviral selectivity. This clearly highlights the Vital role played by the amino acid in the antiviral efficacy of the blocked phosphoramidates.

show abstract

“…We wondered if the activity of such a polar compound might be enhanced by the formation of a more lipophilic alkyl ester. Perhaps such an alkyl H-phosphonate could act as a phosphate prodrug, and deliver the nucleotide intracellularly, as has been implied by studies of a number of blocked phosphates (Farrow et el., 1990;McGuigan et al, 1992a;McGuigan et al, 1993). In the case of the antiherpetic agent ara-A we have found a clear correlation between biological activity and Iipophilicity for a series of dialkyl phosphates, this being attributed to improved membrane penetration by more lipophilic analogues (McGuigan et al, 1989).…”

Section: Introductionmentioning

confidence: 66%

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

View full text Add to dashboard Cite

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.

show abstract

Aryl phosphate derivatives of AZT retain activity against HIV1 in cell lines which are resistant to the action of AZT

Cited by 159 publications

References 16 publications

Certain phosphoramidate derivatives of dideoxy uridine (ddU) are active against HIV and successfully by‐pass thymidine kinase

Certain phosphoramidate derivatives of dideoxy uridine (ddU) are active against HIV and successfully by‐pass thymidine kinase

Phosphoramidates as Potent Prodrugs of anti-HIV Nucleotides: Studies in the Amino Region

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

Contact Info

Product

Resources

About