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Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

  • Andrew J. Wiemer
  • David F. WiemerEmail author
Chapter
Part of the Topics in Current Chemistry book series (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.

Keywords

Bisphosphonate Isoprenoid Nucleotide Phosphate Phosphonate Prodrugs 

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

Notes

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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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesUniversity of ConnecticutStorrsUSA
  2. 2.Departments of Chemistry and PharmacologyUniversity of IowaIowa CityUSA

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