Bioreversible phosphate protective groups: Synthesis and stability of model acyloxymethyl phosphates

Srivastva, Devendra N.; Farquhar, David

doi:10.1016/0045-2068(84)90022-1

Cited by 78 publications

(35 citation statements)

References 8 publications

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“…No intracellular nucleotides were observed with AZT under similar conditions. The proposed mechanism for the intracellular conversion of piv 2 -AZTMP (1) to AZTMP @, deduced from previous studies (Farquhar et al, 1983;Srivastva and Farquhar, 1984;Sastry et al, 1992), is shown in Fig. 1.…”

Section: Introductionmentioning

confidence: 93%

Decomposition Pathways of the Mono- and Bis(Pivaloyloxymethyl) Esters of Azidothymidine 5′-Monophosphate in Cell Extract and in Tissue Culture Medium: An Application of the ‘on-line ISRP-Cleaning’ HPLC Technique

Pompon

Lefèbvre

Imbach

et al. 1994

Antivir Chem Chemother

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Bis(pivaloyloxymethyl) azidothymidine 5'-monophosphate (piv 2-AZTMP) was designed as a cell membrane-permeable precursor of AZTMP. We have reported previously that when incubated with CEM cells deficient in thymidine kinase, piv 2-AZTMP gives rise to intracellular AZTMP and the corresponding diphosphate (AZTDP) and triphosphate (AZTTP). Under similar conditions, no intracellular nucleotides were formed with AZT. However, the mechanism bỹ ich piv 2-AZTMP is converted to AZTMP has not been established. To address this question, we have used the recently developed 'on-line ISRP-cleaning' HPLC technique to investigate the stability and metabolic fate of piv 2-AZTMP (1) in RPMI 1640 medium, (2) in RPMI containing 10% heat-inactivated fetal calf serum, and (3) in CEM cell extracts. Similar studies were conducted starting with mono(pivaloyloxymethyl) azidothymidine 5'-monophosphate (piv 1-AZTMP).From the kinetics of these reactions, it appears that piv 2-AZTMP is slowly hydrolyzed to piv 1-AZTMP in RPMI and that the metabolic sequence in cell extract and in tissue culture medium is clearly: piv 2-AZTMP~piv1-AZTMP~AZTMP~AZT. The rate constants are quite different in these three media. Although it is evident that the first step in the metabolism of piv 2-AZTMP is catalysed by carboxy-. *For correspondence. Tel. +67545873; Fax. +67 0420 29. late esterase, the enzyme(s) responsible for the second step, piv1-AZTMP~AZTMP, is less apparent, as carboxylate esterases and/or phosphodiesterases can be taken in account. However, analysis of the kinetic data strongly suggests that carboxylate esterase does not playa significant role and that this second step is mediated by phosphodiesterases. Collectively, these studies demonstrate, that piv 2-AZTMP is an effective prodrug of AZTMP. They also establish that piv1-AZTMP is an intermediate in this process, and define the sequence of the overall metabolic reaction. With this increased understanding of the metabolism of piv 2-AZTMP, it should be possible rationally to design analogues with optimal structural and pharmacological properties for use in vivo.

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Section: Introductionmentioning

confidence: 93%

Decomposition Pathways of the Mono- and Bis(Pivaloyloxymethyl) Esters of Azidothymidine 5′-Monophosphate in Cell Extract and in Tissue Culture Medium: An Application of the ‘on-line ISRP-Cleaning’ HPLC Technique

Pompon

Lefèbvre

Imbach

et al. 1994

Antivir Chem Chemother

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“…After De Clercq, Holy, Rosenberg and their colleagues reported strong antiviral activity of acyclic nucleoside phosphonates such as 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and ( S ) - 9-(3-hydroxy-2-phosphonyl-methoxypropyl) adenine (( S ) - HPMPA [48] (Reviewed in [49]), the activity of these compounds stimulated great interest in development of prodrug forms to enhance the membrane permeability of these drugs. An early focus was pivaloyloxymethyl (POM) modified phosphonates, a prodrug format that first had been advanced for use with phosphate monoesters [50,51]. However this approach was readily adapted to phosphonates such as foscarnet esters ( 20 ) [52] and a phosphonate inhibitor of insulin receptor tyrosine kinase [53].…”

Section: Ester Prodrugsmentioning

confidence: 99%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

153

135

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A substantial portion of metabolism involves transformation of phosphate esters, including pathways leading to nucleotides and oligonucleotides, carbohydrates, isoprenoids and steroids, and phosphorylated proteins. Because the natural substrates bear one or more negative charges, drugs that target these enzymes generally must be charged as well but small charged molecules can have difficulty traversing the cell membrane other than by endocytosis. The resulting dichotomy has stimulated abundant effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes but then able to release the parent drug once inside the target cell. This chapter will present recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs.

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“…Following literature procedures (Srivastva and Farquhar 1984), 0.05M potassium phosphate buffer (pH 7.4) was placed in a centrifuge tube and a solution of peptide 6 in MeOH was added to achieve a concentration of 200 μM of 6 with MeOH being less than 1%. To a 1 mL aliquot of the above solution was added pig liver esterase (57.6 units) and the reaction mixture was incubated at 37 °C with gentle agitation.…”

Section: Methodsmentioning

confidence: 99%

Design and synthesis of a reagent for solid-phase incorporation of the phosphothreonine mimetic (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) into peptides in a bio-reversible phosphonyl-bis-pivaloyloxymethyl (POM) prodrug form

Qian

Burke

2013

Amino Acids

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Reported herein are the synthesis and solid-phase peptide incorporation of N-Fmoc-(2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid bis-pivaloyloxymethyl phopshoryl ester [Fmoc-Pmab(POM)2-OH, 2] as a phosphatase-stable phosphothreonine (pThr) mimetic bearing orthogonal protection suitable for the synthesis of Pmab-containing peptides having bio-reversible protection of the phosphonic acid moiety. This represents the first report of a bio-reversibly protected pThr mimetic in a form suitable for facile solid-phase peptide synthesis.

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Bioreversible phosphate protective groups: Synthesis and stability of model acyloxymethyl phosphates

Cited by 78 publications

References 8 publications

Decomposition Pathways of the Mono- and Bis(Pivaloyloxymethyl) Esters of Azidothymidine 5′-Monophosphate in Cell Extract and in Tissue Culture Medium: An Application of the ‘on-line ISRP-Cleaning’ HPLC Technique

Decomposition Pathways of the Mono- and Bis(Pivaloyloxymethyl) Esters of Azidothymidine 5′-Monophosphate in Cell Extract and in Tissue Culture Medium: An Application of the ‘on-line ISRP-Cleaning’ HPLC Technique

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Design and synthesis of a reagent for solid-phase incorporation of the phosphothreonine mimetic (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) into peptides in a bio-reversible phosphonyl-bis-pivaloyloxymethyl (POM) prodrug form

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