Selective targeting of 2'-deoxy-5-fluorouridine to urokinase positive malignant cells in vitro

Kara L Vine; Julie M Locke; John B Bremner; Stephen G Pyne; Marie Ranson

doi:10.1016/j.bmcl.2010.03.029

Selective targeting of 2'-deoxy-5-fluorouridine to urokinase positive malignant cells in vitro

Bioorg Med Chem Lett. 2010 May 1;20(9):2908-11. doi: 10.1016/j.bmcl.2010.03.029. Epub 2010 Mar 9.

Authors

Kara L Vine¹, Julie M Locke, John B Bremner, Stephen G Pyne, Marie Ranson

Affiliation

¹ School of Biological Sciences and Centre for Medical Bioscience, University of Wollongong, NSW 2522, Australia. v

PMID: 20363130
DOI: 10.1016/j.bmcl.2010.03.029

Abstract

A urokinase targeting conjugate of 2'-deoxy-5-fluorouridine (5-FUdr) was synthesized and tested for tumor-cell selective cytotoxicity in vitro. The 5-FUdr prodrug 2'-deoxy-5-fluoro-3'-O-(3-carboxypropanoyl)uridine (5-FUdrsuccOH) containing an ester-labile succinate linker was attached to the specific urokinase inhibitor plasminogen activator inhibitor type II (PAI-2) and was found to preferentially kill urokinase-over expressing cancer cells. Up to 7 molecules of 5-FUdr were incorporated per PAI-2 molecule without affecting protein activity. This is the first time a small organic cytotoxin has been conjugated to PAI-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Humans
Neoplasms / enzymology
Plasminogen Activator Inhibitor 2 / chemistry
Plasminogen Activator Inhibitor 2 / metabolism
Uridine / analogs & derivatives*
Uridine / chemical synthesis
Uridine / chemistry
Uridine / toxicity
Urokinase-Type Plasminogen Activator / antagonists & inhibitors
Urokinase-Type Plasminogen Activator / metabolism*

Substances

Plasminogen Activator Inhibitor 2
5-fluorouridine
Urokinase-Type Plasminogen Activator
Uridine