Nucleoside and Nucleotide Prodrugs

Cooperwood, John S.; Gumina, Giuseppe; Boudinot, F. Douglas; Chu, Chung K.

doi:10.1016/b978-044450951-2/50005-9

Cited by 8 publications

(8 citation statements)

References 181 publications

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“…[4,9,12] Unfortunately, the kinetics of the chemical hydrolysis of nucleoside O-aryl-N-alkylphosphoramidates have not previously been studied in such a detailed manner that mechanistic conclusions were possible. The present work is aimed at filling this gap.…”

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

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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.

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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

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“…There are so many review papers about nucleoside chemistry (Huryn et al, 1992), antiviral nucleosides and target of actions (Gumina et al, 2001a;Tan et al, 1999;De Clercq et al, 1994, 1997Hong et al, 1998), and several classes of nucleosides (Crimmins et al, 1998;Zhu et al, 2000;Gumina et al, 2001b;Cooperwood et al, 2002). The action mechanism of antiviral nucleosides may include insertion of the crucial intermediates formed by phosphorylation on 5'-OH into the growing DNA chain.…”

Section: Antiviral Fluorinated Acyclic Nucleosidesmentioning

confidence: 97%

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Kim

2010

Arch. Pharm. Res.

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“…Two types of prodrug approaches exist: bipartate and tripartate approaches [41,42]. In the bipartate prodrug approach, a carrier is linked directly to a pharmacologically active compound.…”

Section: Pronucleotide Approach Generalmentioning

confidence: 99%

“…It should be noted that two of the non-bridging phosphate oxygens are under physiological conditions negatively charged and have to be masked in order to obtain a neutral, lipophilic phosphate ester. Several prodrug strategies have been developed to achieve these goals [41][42][43]. The first attempts were based on the concept of a bipartate prodrug system and simple dialkyl phosphotriesters were used as prodrugs.…”

Section: Pronucleotide Approach Generalmentioning

confidence: 99%

Prodrug Approaches of Nucleotides and Oligonucleotides

Poijärvi-Virta

2006

CMC

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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.

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Nucleoside and Nucleotide Prodrugs

Cited by 8 publications

References 181 publications

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

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

This month in APR

Prodrug Approaches of Nucleotides and Oligonucleotides

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