Synthesis and Evaluation of Some Novel Phosphoramidate Derivatives of 3′-Azido-3′-Deoxythymidine (AZT) as Anti-HIV Compounds

McGuigan, Christopher; Devine, Kevin G.; O’Connor, Tim; Galpin, S.; Jeffries, D. J.; Kinchington, D.

doi:10.1177/095632029000100205

Cited by 58 publications

(34 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MCP104, Vth Int Conf AIDS, Montreal, June 1989). We have noted that simple dialkyl phosphate derivatives of AZT are inactive as anti-HIVagents (McGuigan et al, 1990), whereas certain phosphoramidate analogues are potent inhibitors of viral proliferation (McGuigan et al, 1990b). The initial rationale behind the synthesis of phosphoramidates was the idea that HIV aspartate proteinase (Dunn and Kay, 1990) might specifically hydrolyse these membrane-soluble pro-drugs.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and anti-HIV Activity of Some Novel Phosphorodiamidate Derivatives of 3′-azido-3′-deoxythymidine (AZT)

Jones

McGuigan

O’Connor

et al. 1991

Antivir Chem Chemother

Self Cite

View full text Add to dashboard Cite

SummaryThe reaction of 3'-azido-3'-deoxythymidine (AZT) with phosphoryl chloride followed by amino acid methyl esters gave novel diamidate derivatives of AZT 5'_ monophosphate (AZTMP). It was hoped that the 5'-" phosphorodiamidates might act as membrane-soluble prodrugs of the bio-active free nucleotides of AZT. Five different amino acids were employed, covering a range of structures and polarities. The reaction was also conducted with propylamine, and with diethylamine. The derivatives were tested for their inhibitory effect on human immunodeficiency virus type 1 (HIV-1) proliferation in a human Iymphoblastoid cell line. The amino acid derivatives were potent inhibitors of viral proliferation, small changes in structure leading to marked changes in activity.

show abstract

Section: Introductionmentioning

confidence: 99%

Synthesis and anti-HIV Activity of Some Novel Phosphorodiamidate Derivatives of 3′-azido-3′-deoxythymidine (AZT)

Jones

McGuigan

O’Connor

et al. 1991

Antivir Chem Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, a strategy similar to that we have previously employed for phosphoramidates [9,10] was found to be successful in the case of substituted dialkyl phosphates. Thus, as we have recently noted [6] dodecyl (ethyl glycolyl) phosphorochloridate reacts relatively rapidly with AZT (1) in THF at ambient temperature in the presence of ZV-methylhzidazole [l 13.…”

Section: Chemistrymentioning

confidence: 78%

“…The presence of diastereoisomers was also evident from the "C NMR; indeed the 3:l ratio of isomers allowed an un-equivocal assignment of many of the signals to each of the two structures. As we have noted [9,14], it may well be that the individual diastereoisomers in a particular case may differ in their biological activities; however, in this study the mixtures of isomers were not separated, and were tested as such.…”

Section: Chemistrymentioning

confidence: 97%

Phosphate derivatives of AZT display enhanced selectivity of action against HIV1 by comparison to the parent nucleoside

et al. 1992

View full text Add to dashboard Cite

Novel phosphate derivatives of the and-HIV nucleoside anulogue AZT have been prepared by phosphorochloridate chemistry. In particular, phosphates carrying ester-containing side-chains are described. These materials arc designed 10 act as membrane-soluble prodrugsof the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced, selective anliviral activity. In several cases the phosphate derivatives are more seieclive in their aclhl than the parent nucleoside AZT. In particular, this arises from the low toxicity of the phosphate pro-drugs by comparison to AZT. These data support the suggestion thal the phosphate derivatives exert their biological effects via intracellular release of the nuclcotide forms, and suggests that such pro-drug forms may be worthy of further study.

show abstract

“…More recently, it has been noted that analogous bis(trihaloalkyl) phosphate derivatives of araA and araC have potent biological properties (McGuigan et al, 1992a). Moreover, some phosphoramldate derivatives of AZT act as antiviral agents (Devine et al, 1990;McGuigan et al, 1990c), and certain combinations of haloalkyl chains and N-Iinked amino acid esters are especially efficacious (McGuigan et al, 1991). Other researchers have noted the efficacy of bis(acyloxy)methyl phosphates (Freed et al, 1989) and of asymmetric phosphates, carrying carbohydrate and lipid groups (Henin et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Haloalkyl Phosphate Derivatives of AZT as Inhibitors of HIV: Studies in the Phosphate Region

McGuigan

Turner²,

Nicholls

et al. 1994

Antivir Chem Chemother

Self Cite

View full text Add to dashboard Cite

Novel haloalkyl phosphate derivatives of the anti-HIV nucleoside analogue AZT were prepared by phosphorochloridate chemistry. These materials were designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced and selective antiviral action, which varied greatly with the structure of the phosphate moiety. By comparison to simple dialkyl phosphates, which are inactive against HIV-1, the introduction of halogen atoms into the alkyl (phosphate) chains led to anti-HIV activity. Although halogen substitution in just one alkyl chain was sufficient for biological activity, substitution in the second alkyl chain further enhanced activity. Conversely, stabilization of the second chain, by conversion to a phosphonate, led to a reduction in activity. In one case, the diastereo-isomers resulting from mixed stereochemistry at the phosphate centre were separated, and found to differ in activity by one order of magnitude. Lastly, the bis(mono- and di-chloroethyl) phosphates were prepared and found to display moderate anti-HIV activity.

show abstract

Synthesis and Evaluation of Some Novel Phosphoramidate Derivatives of 3′-Azido-3′-Deoxythymidine (AZT) as Anti-HIV Compounds

Cited by 58 publications

References 23 publications

Synthesis and anti-HIV Activity of Some Novel Phosphorodiamidate Derivatives of 3′-azido-3′-deoxythymidine (AZT)

Synthesis and anti-HIV Activity of Some Novel Phosphorodiamidate Derivatives of 3′-azido-3′-deoxythymidine (AZT)

Phosphate derivatives of AZT display enhanced selectivity of action against HIV1 by comparison to the parent nucleoside

Haloalkyl Phosphate Derivatives of AZT as Inhibitors of HIV: Studies in the Phosphate Region

Contact Info

Product

Resources

About