Abstract
A series of novel haloethyl and piperidyl phosphoramidate FdUMP prodrug analogues has been synthesized, and the growth inhibitory activity of these compounds has been evaluated against L1210 mouse leukemia cells. All compounds exhibited potent inhibition of L1210 cell proliferation with IC50 values in the nanomolar range. Growth inhibition was reversed by the addition of 5 μM thymidine, suggesting a mechanism of action involving the intracellular release of FdUMP. 31P NMR studies carried out on model haloethyl phosphoramidates confirm the release of nucleotide via cyclization of the phosphoramidate anion to the aziridinium ion intermediate followed by hydrolysis of the P-N bond. The data suggests that <50% of the prodrug is converted to FdUMP intracellularly by this pathway. Piperidyl phosphoramidate analogues are also converted to nucleotide intracellularly, presumably by the action of an endogenous phosphoramidase.
Original language | English (US) |
---|---|
Pages (from-to) | 4313-4318 |
Number of pages | 6 |
Journal | Journal of medicinal chemistry |
Volume | 43 |
Issue number | 22 |
DOIs | |
State | Published - Nov 2 2000 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery