1992
DOI: 10.1016/0166-3542(92)90026-2
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Aryl phosphate derivatives of AZT retain activity against HIV1 in cell lines which are resistant to the action of AZT

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Cited by 159 publications
(138 citation statements)
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“…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%
See 1 more Smart Citation
“…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%
“…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%
“…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%