5-Deoxyuridine fluoro-, prodrugs

The novel 5-fluoro-2 -deoxyuridine phosphoramidate prodrug 195 has been prepared, along with the compound with only one bromoethyl group. The... 

An interesting dinically useful prodrug is 5-fluorouracil, which is converted in vivo to 5-fluoro-2 -deoxyuridine 5 -monophosphate, a potent irreversible inactivator of thymidylate synthase It is sometimes charaderized as a dead end inactivator rather than a suicide substrate since no electrophile is unmasked during attempted catalytic turnover. Rathei since a fluorine atom replaces the proton found on the normal substrate enzyme-catalyzed deprotonation at the 5 -position of uracil cannot occur. The enzyme-inactivator covalent addud (analogous to the normal enzyme-substrate covalent intermediate) therefore cannot break down and has reached a dead end (R. R. Rando, Mechanism-Based Enzyme Inadivators , Pharm. Rev. 1984,36,111-142). 

Fig. 42 Prodrug [128] is an acylated derivative of the anticancer drug 5-fluoro-deoxyuridine. Antibody 49.AG.659.12, raised against phosphonate [127] was found to activate the prodrug [128] in vitro, thereby inhibiting the growth of E. coli.

Seki, T., Kawaguchi, T., et al. Controlled release of 3, 5 -diester prodrugs of 5-fluoro-2 -deoxyuridine from poly-L-lactic acid microspheres. J. Pharm. Sci. 79(ll) 985-987,1990. 

Fluorouracil (5-FU) is a prodrug and undergoes a complex series of biotransformation reactions to ribosyl and deoxyribosyl nucleotide metabolites. One of these metabolites, 5-fluoro-2 -deoxyuridine-5 -monophosphate (FdUMP), forms a covalently bound ternary complex with the enzyme thymidylate synthase and the reduced folate A510-methylenetetrahydrofolate, a reaction critical for the synthesis of thymidylate. This results in inhibition of DNA synthesis through "thymineless death." 5-FU is converted to 5-fluorouridine-5 -triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and mRNA translation. In... 

I. J., and Harris, A. L. (1995) Increased sensitivity to the prodrug 5 -deoxy-5-fluorouridine and modulation of 5-fluoro-2 -deoxyuridine sensitivity in MCF-7 cells transfected with thymidine phosphorylase. Br. J. Cancer 72, 669-675. 

Capecitabine is a pyrimidine analog. It is an oral systemic prodrug that is enzymatically converted to 5-fluorouracil (5-FU). Healthy and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-flu-orouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, they inhibit the formation of thymidine triphosphate, which is essential for the synthesis of DNA. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis. Capecitabine is indicated in the treatment of resistant metastatic breast cancer alone or in combination with docetaxel, and colorectal cancer. 

This deoxyribonucleoside prodrug (Fig. 42.26) is bioconverted via 2 -deoxyuridine kinase-mediated phosphorylation to the same active 5-fluoro-dUMP structure generated in the multistep biotransformation of... 

The ester 246 has been prepared as a potential bioreductively-activated prodrug of 5-fluoro-2 -deoxyuridine (FUDR). It was resistant to human serum esterases due to the steric hindrance of the a-methyl groups, but chemical reduction led to rapid release of FUDR by intramolecular aminolysis. ... 

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