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T. I. Kalman and L. Lai
of the 5-fluoropyrimidines, an important class of anticancer drugs (Figure 4). It is
responsible for the activation of 5-fluorouracil (FU) and its prodrug derivatives,
capecitabin, 5’-fluoro-2’-deoxyuridine and tegafur, as well as the moderate
selectivity of these prodrugs. In contrast, it curtails the utility of the more potent
and DNA-selective 5-fluoro-2’-deoxyuridine (FdUrd), by rapidly converting it to FU.
Thus, TP inhibitors cannot be combined with FU and its prodrugs. However, their
combination with FdUrd may have potential therapeutic benefit by preventing the
metabolic degradation of this drug. It should be noted that due to the presence of
their 6-substituent, the fluoropyrimidines 21--23 described in this paper are not
subject to the metabolism outlined in Figure 4. Thus, these TP inhibitors represent a
new class of 5-fluoropyrimidines with a novel mechanism of action.
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