Synthesis and biological evaluation of a cytarabine phosphoramidate prodrug.

Abstract

Recently, we reported a novel approach for the intracellular delivery of the anti-cancer nucleotide 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) using phosphoramidate-based prodrugs. These phosphoramidate prodrugs contain an ester group that undergoes intracellular activation, liberating phosphoramidate anion, which in turn undergoes spontaneous cyclization and P-N bond cleavage to yield the nucleoside monophosphate quantitatively. This approach has now been extended to cytarabine [1-beta-D-arabinofuranosylcytosine (Ara-C)], an anti-cancer nucleoside that is limited in its utility because of poor intracellular transport characteristics and weak activity as a substrate for tumor cell kinases. The cytarabine phosphoramidate prodrug 1 has been synthesized and evaluated in comparison with cytarabine for growth inhibitory activity against wild-type, nucleoside transport-deficient, and nucleoside kinase-deficient CEM leukemia cell lines. The prodrug was comparable in growth inhibitory activity (IC50 = 32 nM) to cytarabine (IC50 = 16 nM) in wild-type CCRF-CEM cells following drug treatment for 72 h. The nucleoside transport-deficient CEM/AraC8C exhibited a high level of resistance (6400-fold) to cytarabine but was more sensitive (210-fold resistant vs CCRF-CEM cells) to prodrug 1. Similarly, the deoxycytidine kinase-deficient cell line (CEM/dCK-) was highly resistant to cytarabine (13900-fold) but more sensitive (106-fold resistant vs CCRF-CEM cells) to prodrug 1. These results indicate that prodrug 1 is significantly more potent than cytarabine against transport- and kinase-deficient cell lines and are consistent with a mechanism involving intracellular delivery of cytarabine 5'-monophosphate.

• Authors: Sandra C Tobias, Richard F Borch
• Journal: Molecular pharmaceutics (Mol Pharm) 2004 Mar-Apr Vol. 1 Issue 2 Pg. 112-6 ISSN: 1543-8384 [Print] United States
• PMID: 15832507 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amides
• Phosphoric Acids
• Prodrugs
• Cytarabine
• phosphoramidic acid

Topics

• Amides (chemical synthesis, pharmacology)
• Biological Transport
• Cell Division
• Cell Line, Tumor
• Cytarabine (chemical synthesis, pharmacology)
• Humans
• Magnetic Resonance Spectroscopy
• Phosphoric Acids (chemical synthesis, pharmacology)
• Prodrugs (chemical synthesis, pharmacology)