Synthesis and biological evaluation of a cytarabine phosphoramidate prodrug
| Autor: | Richard F. Borch, Sandra C. Tobias |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Magnetic Resonance Spectroscopy
Stereochemistry Pharmaceutical Science chemistry.chemical_compound Cell Line Tumor Drug Discovery medicine Humans Nucleotide Phosphoric Acids Prodrugs chemistry.chemical_classification Kinase Cytarabine Phosphoramidate Biological Transport Prodrug Amides Deoxyuridine Biochemistry chemistry Molecular Medicine Nucleoside Intracellular Cell Division medicine.drug |
| Zdroj: | Molecular pharmaceutics. 1(2) |
| ISSN: | 1543-8384 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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