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Phosphorus Chemistry I pp 115–160Cite as

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

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Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 360))

Abstract

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 by means other than endocytosis. The resulting dichotomy has stimulated a great deal of effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes, but able to release the parent drug once inside the target cell. This chapter presents recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs.

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Abbreviations

AraC:

Arabinofuranosylcytidine

AZT:

Azidothymidine

CMV:

Cytomegalovirus

d4TMP:

2′,3′-Didehydro-3′-dideoxy-thymidine-5′-monophosphate

DOXP:

1-Deoxy-d-xylulose 5-phosphate

EBV:

Epstein–Barr virus

GCPR:

G protein coupled receptor

GemC:

Gemcitabine

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

HDP:

Hexadecyloxypropyl

HIV:

Human immunodeficiency virus

HPMPA:

9-(3-Hydroxy-2-phosphonyl-methoxypropyl)adenine

HSV:

Herpes-simplex virus

NA:

Nucleoside analogue

PMEA:

9-[2-(Phosphonomethoxy)ethyl]adenine

POC:

Isopropyloxycarbonyloxymethyl

POM:

Pivaloyloxymethyl

RBV:

Ribavirin

SATE:

S-Acylthioalkyl ester

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Acknowledgements

Financial support from the University of Connecticut, Department of Pharmaceutical Sciences (AJW) and from the Roy J. Carver Charitable Trust as a Research Program of Excellence (DFW) and the NIH (R01CA-172070, DFW) is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA

    Andrew J. Wiemer

  2. Departments of Chemistry and Pharmacology, University of Iowa, Iowa City, IA, 52242-1294, USA

    David F. Wiemer

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Correspondence to David F. Wiemer .

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  1. Department of Chemistry, Texas Christian University, Fort Worth, Texas, USA

    Jean-Luc Montchamp

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Wiemer, A.J., Wiemer, D.F. (2014). Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier. In: Montchamp, JL. (eds) Phosphorus Chemistry I. Topics in Current Chemistry, vol 360. Springer, Cham. https://doi.org/10.1007/128_2014_561

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