Synthesis, in vitro anti-breast cancer activity, and intracellular decomposition of amino acid methyl ester and alkyl amide phosphoramidate monoesters of 3'-azido-3'-deoxythymidine (AZT).

doi:10.1021/JM000110G

Paper

Synthesis, in vitro anti-breast cancer activity, and intracellular decomposition of amino acid methyl ester and alkyl amide phosphoramidate monoesters of 3'-azido-3'-deoxythymidine (AZT).

Published Jun 1, 2000 · V. Iyer, G. Griesgraber, Matthew R. Radmer

Journal of medicinal chemistry

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45

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Abstract

We report the synthesis and anticancer activity of a series of AZT phosphoramidate monoesters containing amino acid methyl ester (3a-11a) and N-alkyl amide (3b-11b, 9c-9f) moieties. The aromatic amino acid methyl esters were found to be more cytotoxic than the aliphatic analogues toward MCF-7 cells (human pleural effusion breast adenocarcinoma cell line). A marked stereochemical preference for the L-amino acid stereochemistry was also observed in MCF-7 cells. There was no consistent enhancement of cytotoxicity of the methyl amides over the corresponding methyl esters. AZT and the two AZT aromatic amino acid methyl ester phosphoramidates 8a and 9a were found to be more cytotoxic toward MCF-7 cells than to CEM cells (human T-cell lymphoblastic leukemia). The selective cytotoxicity toward MCF-7 cells may be associated with greater intracellular levels of phosphoramidate monoester and/or phosphorylated AZT.

In Vitro Study

Study Snapshot

AZT phosphoramidate monoesters with aromatic amino acid methyl esters show greater cytotoxicity against MCF-7 breast cancer cells than their aliphatic analogues, suggesting potential for anti-breast cancer therapy.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Paper

Synthesis, in vitro anti-breast cancer activity, and intracellular decomposition of amino acid methyl ester and alkyl amide phosphoramidate monoesters of 3'-azido-3'-deoxythymidine (AZT).

References

Antiviral nucleoside drug delivery via amino acid phosphoramidates.

Stable and water soluble amino acid phosphoramidates of AZT show potent anti-HIV-1 activity and have a 5-fold greater half life and tissue distribution than AZT itself.

A new synthetic method for the preparation of nucleoside phosphoramidate analogues with the nitrogen atom in bridging positions of the phosphoramidate linkage

This study presents a new synthetic method for preparing nucleoside phosphoramidate analogues with nitrogen atoms in bridging positions, enabling the preparation of nucleoside P3′-N5′ and N3′-P5′ phosphoramidates and their thio

Probing the mechanism of action and decomposition of amino acid phosphomonoester amidates of antiviral nucleoside prodrugs.

AZT phosphomonoester amidates show comparable antiviral activity to AZT, with their decomposition pathway differing from that of amino acid carbomethoxy ester aryl phosphodiester amidates.

Human Immunodeficiency Virus Resistance to AZT in MOLT4/8 Cells is Associated with a Lack of AZT Phosphorylation and is Bypassed by AZT-Monophosphate SATE Prodrugs

MOLT4/8rAZT250 cells exhibit resistance to AZT's anti-HIV activity due to lack of phosphorylation, but resistance can be bypassed using AZT-monophosphate SATE prodrugs.

Potent growth inhibitory activity of zidovudine on cultured human breast cancer cells and rat mammary tumors.

AZT has significant anti-breast cancer activity, with a 1000-fold higher inhibitory effect on human breast cancer cells and a similar effect in rat mammary tumors.

Citations

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Chemopreventive efficacy of stampidine in a murine breast cancer model

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Rational approaches, design strategies, structure activity relationship and mechanistic insights for therapeutic coumarin hybrids.

Therapeutic coumarin hybrids show potential for treating complex disorders by combining coumarin moiety with other therapeutic pharmacophores.

Reaction of β-alkoxyvinyl α-ketoesters with acyclic NCN binucleophiles – Scalable approach to novel functionalized pyrimidines

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