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

McGuigan, Christopher; Cahard, Dominique; Salgado, Antonio; Clercq, Erik De; Balzarini, Jan

doi:10.1177/095632029600700106

Cited by 20 publications

(23 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This reinforces our recent observation that the nature of the amino moiety is crucial for the eventual antiviral action, with simple amines being completely unable to substitute for amino acids (McGuigan et al, 1996b). Interestingly, even though the D-triester 4 is relatively poorly active (EC so ",,211M), it does appear to retain full activity in thymidine kinase-deficient cells, again in marked contrast to the parent nucleoside analogue 3; indeed it is ",,1 O-fold more potent than d4T in these cells.…”

supporting

confidence: 74%

Novel Nucleoside Phosphoramidates as Inhibitors of HIV: Studies on the Stereochemical Requirements of the Phosphoramidate Amino Acid

McGuigan

Salgado

Yarnold

et al. 1996

Antivir Chem Chemother

Self Cite

View full text Add to dashboard Cite

SummaryNovel phosphoramidate derivatives of the anti-HIV nucleoside analogue d4T were designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotide d4TMP. We herein reveal the very marked dependence of the antiviral activity of these phosphoramidates upon the stereochemistry of the amino acid attached to the phosphate centre; with a strong preference for the L-stereochemistry. These phosphate trlesters were shown to liberate amino acid derivatives of the nucleotide intracellularly. These novel analogues, typified by alaninyl d4T monophosphate, may act as intracellular sources of the free nucleotides. The alaninyl d4T adducts themselves exert an antiviral effect when administered extracellularly, but again with clear distinctions between the L-and D-series. This evidence indicates that extracellularly administered blocked triesters derived from L-amino acids can generate d4TMP lntracellularly, by a new pathway which is highly dependent on the amino acid stereochemistry.

show abstract

supporting

confidence: 74%

Novel Nucleoside Phosphoramidates as Inhibitors of HIV: Studies on the Stereochemical Requirements of the Phosphoramidate Amino Acid

McGuigan

Salgado

Yarnold

et al. 1996

Antivir Chem Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…The a-amino acid moiety appears to be essential, since phosphoramidates derived from simple alkylamines or b-amino acids do not show antiviral activity. [10] The release of the monophosphate probably proceeds by intermediate formation of l-alaninyl phosphoramidate 2.…”

Section: Introductionmentioning

confidence: 99%

Hydrolytic Reactions of Thymidine 5′‐O‐Phenyl‐N‐Alkylphosphoramidates, Models of Nucleoside 5′‐Monophosphate Prodrugs

Ora

Ojanperä

Lönnberg

2007

Chemistry A European J

View full text Add to dashboard Cite

To obtain detailed data on the kinetics of hydrolytic reactions of triester-like nucleoside 5'-O-aryl-N-alkylphosphoramidates, potential prodrugs of antiviral nucleoside monophosphates, the hydrolysis of diastereomeric (Rp/Sp) thymidine 5'-{O-phenyl-N-[(1S)-2-oxo-2-methoxy-1-methylethyl]phosphoramidate} (3), a phosphoramidate derived from the methyl ester of L-alanine, has been followed by reversed-phase HPLC over the range from Ho=0 to pH 8 at 90 degrees C. According to the time-dependent product distributions, the hydrolysis of 3 proceeds at pH<4 by two parallel routes, namely by nucleophilic displacement of the alaninyl ester moiety by a water molecule and by hydrolysis of the carboxylic ester linkage that allows intramolecular attack of the carboxy group on the phosphorus atom, thereby resulting in the departure of either thymidine or phenol without marked accumulation of any intermediates. Both routes represent about half of the overall disappearance of 3. The departure of phenol eventually leads to the formation of thymidine 5'-phosphate. At pH>5, the predominant reaction is hydrolysis of the carboxylic ester linkage followed by intramolecular displacement of a phenoxide ion by the carboxylate ion and hydrolysis of the resulting cyclic mixed anhydride into an acyclic diester-like thymidine 5'-phosphoramidate. The latter product accumulated quantitatively without any indication of further decomposition. Hydroxide-ion-catalyzed P--OPh bond cleavage of the starting material 3 occurred as a side reaction. Comparative measurements with thymidine 5'-{N-[(1S)-2-oxo-2-methoxy-1-methylethyl]phosphoramidate} (4) revealed that, under acidic conditions, this diester-like compound is hydrolyzed by P--N bond cleavage three orders of magnitude more rapidly than the triester-like 3. At pH>5, the stability order is reversed, with 3 being hydrolyzed six times as rapidly as 4. Mechanisms of the partial reactions are discussed.

show abstract

“…The purpose is to increase the extracellular stability without retarding the intracellular conversion to active drug. Acyclic and Cyclic Phosphoramidate Pronucleotides antiviral activity [93]. Among various α-amino acid derivatives, L-alanine has been found to be the most efficient antiviral agent, while the enantiomeric D-alanine exhibits a 30-fold lower activity.…”

Section: Fig (2)mentioning

confidence: 99%

Prodrug Approaches of Nucleotides and Oligonucleotides

Poijärvi-Virta

2006

CMC

View full text Add to dashboard Cite

The main threshold for the therapeutic applications of nucleotides and oligonucleotides is their ionic structure which implies poor cellular uptake and unfavorable pharmacokinetic parameters. To circumvent these problems, the anionic phosphate moieties may be temporarily masked with enzymolabile protecting groups to form neutral pronucleotides or pro-oligonucleotides. In cells, enzymes cleave the protecting groups and release the parent drug. Several prodrug strategies have been developed, but the kinetics and mechanisms of the deprotection of potential prodrug candidates are still often poorly known. The purpose of the present review is to summarize the current knowledge on the chemical aspects of alternative prodrug strategies at nucleotide and oligonucleotide level.

show abstract

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

Cited by 20 publications

References 19 publications

Novel Nucleoside Phosphoramidates as Inhibitors of HIV: Studies on the Stereochemical Requirements of the Phosphoramidate Amino Acid

Novel Nucleoside Phosphoramidates as Inhibitors of HIV: Studies on the Stereochemical Requirements of the Phosphoramidate Amino Acid

Hydrolytic Reactions of Thymidine 5′‐O‐Phenyl‐N‐Alkylphosphoramidates, Models of Nucleoside 5′‐Monophosphate Prodrugs

Prodrug Approaches of Nucleotides and Oligonucleotides

Contact Info

Product

Resources

About