Synthesis and anti-HIV activity of some novel lactyl and glycolyl phosphate derivatives

McGuigan, Christopher; Nickson, Caleb; O'Connor, Timothy J.; Kinchington, D.

doi:10.1016/0166-3542(92)90041-3

Cited by 16 publications

(15 citation statements)

References 14 publications

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“…In particular, in contrast to AZT, the agents are selective, less toxic, antiviral agents in vitro. One of the products herein reported (3a) was recently described by us [6]. However, its activity is now described in a new assay, where it is included alongside new agents described here for the first time.…”

Section: Introduction 2 Materlals and Methodsmentioning

confidence: 99%

“…; [S], and very recently we have noted the activity of cstersubstituted alkyd phosphates [6]. However, in the former report both alkyl groups were substituted, whilst in the latter only one group was ester-containing, the other group being a simple alkyl moiety.…”

Section: Chemistrymentioning

confidence: 99%

“…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. The target product (3a) was isolated in moderate yield and fully characterised by a range of spectroscopic methods.…”

Section: Chemistrymentioning

confidence: 99%

“…This was prepared entirely as recently described by US [6]. Ethyl glycolyl methyl lactyl phosphorochloridate (1.62 g, 1.5 ml, 0.006 mol) was addtxl to AZT (0.25 g, 0.94 mmol) and N-methylimidazole (0.61 g, 0.55 ml, 0.007 mol) in tetrabydrofuran (5 ml) wirh stirring at room temperature.…”

Section: 'Arido-y-dcoxythynidine-y-dodccy F (Etfty F Glycoly!) Pltumentioning

confidence: 99%

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

et al. 1992

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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.

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Section: Introduction 2 Materlals and Methodsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: 'Arido-y-dcoxythynidine-y-dodccy F (Etfty F Glycoly!) Pltumentioning

confidence: 99%

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

et al. 1992

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“…In addition, the high polarity of these compounds further reduces cell uptake. Phosphotriester derivatives, such as O-alkyl-5'-5'-dinucleotide phosphates, in which AZT is linked to cordycepin (Meier and Huynh Dinh, 1991) are less polar as are phosphotriesters of AZT with lactyl or glycolyl phosphates (McGuigan et al, 1992). Even if the cellular uptake of these prodrugs is more efficient than that of AZT-5'" monophosphate, the enzymatic release of the active moiety of the prodrug is probably inhibited by the unnatural triester linkage.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, and Some Properties of, Amphiphilic Dinucleoside Phosphate Derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT)

Schott

Häussler

Gowland

et al. 1994

Antivir Chem Chemother

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N4-hexadecyl-5′-0-(4-monomethoxytrityl)-2′-deoxycytidine-3′-hydrogenphosphate was reacted with 3′-azido-2′,3′-dideoxythymidine (AZT) according to the hydrogenphosphate method to yield N4-hexadecyl-2′-deoxycytidylyl-(3′-5)-3′-azido-2′,3′-dideoxythymidine. N4-palmitoyl-5′-O-(4-monomethoxytrityl)-2′-deoxycytidine-3′-(2-chlorophenyl)-phosphate was condensed to AZT using the triester method to give N4-palmitoyl-2′-deoxycytidylyl-(3′-5′)-3,-azido-2′,3′-dideoxythymidine. Both dinucleosidephosphates have amphiphilic properties and represent a new class of AZT derivatives in which the polar AZT-5′-monophosphate is masked with lipophilic deoxycytidine residues of variable stability. The AZT derivatives are water soluble, by forming micelles, and as a result of their amphiphilic nature, they can be incorporated into the lipid membranes of liposomes. In contrast to the micellar drug preparations, the liposomal formulations were shown to exert no lytic activity on human erythrocytes. Both AZT derivatives have anti HIV-1 activity in vitro.

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Nucleotide Delivery fromcycloSaligenyl-3′-azido-3′-deoxythymidine Monophosphates (cycloSal-AZTMP)

Meier¹,

Clercq

Balzarini

1998

Eur. J. Org. Chem.

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The application of our cycloSaligenyl‐ (cycloSal) pronucleotide concept to the approved anti‐HIV dideoxynucleoside 3′‐azido‐3′‐deoxythymidine AZT (1) is reported. This pro‐nucleotide concept has been designed to deliver the corresponding 3′‐azido‐3′‐deoxythymidine monophosphate AZTMP (2) by selective chemical hydrolysis from the lipophilic precursors cycloSal‐AZTMP 4a−h. All derivatives 4a−h were synthesized using differently substituted salicyl alcohols 7a−h as starting materials. In hydrolysis studies, compounds 4 decomposed selectively releasing AZTMP (2) and the salicyl alcohols 7 following the designed tandem reaction. Furthermore, due to the electronic properties introduced by substituents, the half‐lives of the triesters 4 could be ajusted over a wide range. Phosphotriesters 4 exhibited considerable biological activity in HIV‐1 and HIV‐2 infected wild‐type human T‐lymphocyte (CEM/O) cells, whereas, contrary to our expectations, nearly all activity was lost in HIV‐2 infected thymidine‐kinase‐deficient CEM cells.

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Synthesis and anti-HIV activity of some novel lactyl and glycolyl phosphate derivatives

Cited by 16 publications

References 14 publications

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

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

Synthesis, and Some Properties of, Amphiphilic Dinucleoside Phosphate Derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT)

Nucleotide Delivery fromcycloSaligenyl-3′-azido-3′-deoxythymidine Monophosphates (cycloSal-AZTMP)

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