Prodrugs of Analogs of Nucleic Acid Components

Alexander, P.; Holý, Antonı́n

doi:10.1135/cccc19942127

Cited by 22 publications

(9 citation statements)

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“…Unfortunately, this problem cannot be resolved by use of nucleotides which cannot penetrate the cell membrane because of their polar nature, and their rapid dephosphorylation in extracellular fluids and on cell surfaces (Leibman and Heideberg, 1955;Roll et al, 1956;Lichtenstein et al, 1960). Thus, in order to overcome this limitation, many strategies have been devised to mask or to reduce the phosphate negative charges of nucleoside 5'-monophosphate analogues with neutral substituents, thereby forming more lipophilic derivatives (pronucleotides) which would be expected to revert back to the corresponding 5'-mononucleotides once inside the cell (Alexander and Holy, 1994;Perigaud et al, 1995). Our group has recently reported the study of neutral mononucleoside phosphotriesters which incorporate biolabile Sacyl-2-thioethyl (SATE) phosphate protecting groups (Lefebvre et et., 1995).…”

Section: Introductionmentioning

confidence: 99%

Comparison of Cytotoxicity of Mononucleoside Phosphotriester Derivatives Bearing Biolabile Phosphate Protecting Groups in Normal Human Bone Marrow Progenitor Cells

Philouze

Girardet

Lefèbvre

et al. 1996

Antivir Chem Chemother

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SummaryThe effects of three mononucleoside phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) which incorporate biolabile phosphate protecting groups, namely 5-acetyl-2-thioethyl (MeSATE), 5-(2-hydroxyethylsulfidyl)-2-thioethyl (OTE), and pivaloyloxymethyl (POM) were studied and compared to their nucleoside parent in human myeloid colony-forming cells. Moreover, the relative antiviral potency of these three pronucleotldes were determined in primary human peripheral blood mononuclear cells infected with human immunodeficiency virus type 1. The results indicate that the SATE and OTE pro-moieties, as well as their degradation products, do not induce additional toxicity. The bis(MeSATE) phosphotriester derivative of AZT emerged as the most selective inhibitor with an in-vitro therapeutic index of the same order of magnitude as observed for AZT. This study has been extended to the corresponding bis(MeSATE) and bis(OTE) phosphotriester derivatives of 2',3'-dideoxyuridine (ddU).

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Section: Introductionmentioning

confidence: 99%

Comparison of Cytotoxicity of Mononucleoside Phosphotriester Derivatives Bearing Biolabile Phosphate Protecting Groups in Normal Human Bone Marrow Progenitor Cells

Philouze

Girardet

Lefèbvre

et al. 1996

Antivir Chem Chemother

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“…PMEApp and PMPApp inhibit adenylyl cyclase in vitro (IC 50 values ϳ175 and 500 nM, respectively; Table I). Because PMEApp and PMPApp inhibit viral reverse transcriptase in vitro, and protected precursor forms of PMEA and PMPA inhibit viral reverse transcriptase activity in intact cells (25)(26)(27)(28)(29), it was expected that protected forms of PMEA and PMPA would also have inhibited adenylyl cyclase in intact cells, but they did not. It was similarly expected that protected derivatives of ␤-L-2Ј,3Ј-dd-5Ј-AMP would reduce adenylyl cyclase in intact cells.…”

Section: Discussionmentioning

confidence: 99%

“…Although cell-permeable, adenine nucleosides are much less potent than the corresponding nucleoside polyphosphates, and because of the relatively high concentrations needed to inhibit adenylyl cyclases may have unintended side effects (2-4, 6, 7, 11, 19 -24). To circumvent the general problem of poor permeability of nucleotides in intact cells, biodegradable lipophilic groups have been chemically linked to nucleoside phosphate group(s), giving families of pro-nucleotides that are uncharged and membrane-permeable (25)(26)(27)(28)(29). These are typically nucleoside monophosphates with a protected phosphate group, with protection being afforded by any of several substituents (30 -37).…”

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confidence: 99%

“…First, it is cell-permeable. Second, the otherwise highly selective and often rate-limiting initial phosphorylation of a nucleoside is bypassed because the nucleoside monophosphate has been transported into the cell (25)(26)(27)(28)(29)(30)(31). The nucleoside monophosphate can then readily be phosphorylated by intracellular enzymes to the corresponding polyphosphate, often the most potent and desired form.…”

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confidence: 99%

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Pro-nucleotide Inhibitors of Adenylyl Cyclases in Intact Cells

Laux

Pande

Shoshani

et al. 2004

Journal of Biological Chemistry

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9-Substituted adenine derivatives with protected phosphoryl groups were synthesized and tested as inhibitors of adenylyl cyclase in isolated enzyme and intact cell systems. Protected 3-phosphoryl derivatives of 2,5-dideoxyadenosine (2,5-dd-Ado) and ␤-L-2,5-ddAdo, protected 5-phosphoryl derivatives of ␤-L-2,3-ddAdo, and protected phosphoryl derivatives of two 9-(2-phosphonomethoxy-acyl)-adenines were synthesized. Protection was afforded by two cyclosaligenyl-or three S-acyl-2-thioethyl-substituents. These pro-nucleotides were tested for their capacity to block forskolin-induced increases in [ 3 H]cAMP in OB1771 and F442A preadipocytes and human macrophages prelabeled with [ 3 H]adenine. A striking selectivity for 2,5-dd-Ado-3-phosphoryl derivatives was observed. Cyclosaligenyl-derivatives (IC 50 ϳ2 M) were much less potent than S-acyl-2-thioethyl-derivatives. Best studied of these was 2,5-dd- Ado-3-O-bis(S-pivaloyl-2-thioethyl)-phosphate, which blocked [3 H]cAMP formation in preadipocytes (IC 50 ϳ30 nM) and suppressed opening of cAMP-dependent Cl ؊ channels in cardiac myocytes (IC 50 ϳ800 nM). None of the pro-nucleotides inhibited adenylyl cyclase per se, whether isolated from rat brain or OB1771 cells. These compounds exhibit the hallmarks of prodrugs. Data suggest they are taken up, are deprotected, and are converted to a potent inhibitory form to inhibit adenylyl cyclase, but only by intact cells. The availability and characteristics of these prodrugs should make them useful for blocking cAMP-mediated pathways in intact cell systems, in biochemical, pharmacological, and potentially therapeutic contexts.

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“…Several successful approaches to deliver 5'-monophosphates of anti-HIV drugs directly into cells were recently reported[48][49][50][51][52][53][54]. Modifications of the phosphate moiety of nucleotide…”

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confidence: 99%

Design of Anti-HIV Compounds from Nucleoside to Nucleoside 5-Triphosphate Analogs. Problems and Perspectives

Kukhanova¹,

Krayevsky²,

Prusoff³

et al. 2000

CPD

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To date, human immunodeficiency virus infection remains incurable although a variety of antiviral agents have been identified and characterized. Even though nucleoside analogs have been the most successful prodrugs, there remains the need to develop new compounds that exhibit a more favorable toxicity profile, less susceptible to cross-resistance, and greater efficacy. As prodrugs, the nucleoside analogs should be sequentially phosphorylated by cellular kinases to yield triphosphate form before they can inhibit HIV replication at the reverse transcriptase level. The efficiency of phosphorylation of nucleoside analogs is a key factor in their antiviral activity and strongly depends on nucleoside structure and cell type. In recent years, several attempts have been made to improve therapeutic potential of nucleoside analogs by the use of nucleotide prodrugs (pronucleotides), that can avoid the first step of phosphorylation. This review focuses on problems of intracellular phosphorylation of nucleoside analogs and perspectives of developing of a new class of nucleotide analogs modified at phosphate group as a form for the delivery of nucleotide analogs into the cell.

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Prodrugs of Analogs of Nucleic Acid Components

Cited by 22 publications

References 0 publications

Comparison of Cytotoxicity of Mononucleoside Phosphotriester Derivatives Bearing Biolabile Phosphate Protecting Groups in Normal Human Bone Marrow Progenitor Cells

Comparison of Cytotoxicity of Mononucleoside Phosphotriester Derivatives Bearing Biolabile Phosphate Protecting Groups in Normal Human Bone Marrow Progenitor Cells

Pro-nucleotide Inhibitors of Adenylyl Cyclases in Intact Cells

Design of Anti-HIV Compounds from Nucleoside to Nucleoside 5-Triphosphate Analogs. Problems and Perspectives

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