5-fluoro-2 -deoxyuridylic acid

Fluorodl is metabolized by the same route to 5-fluoro- — 2-deoxyuridylic acid (FUdRP)... 

Ludwig P S, Schwendener R A, Schott H (2005). Synthesis and anticancer activities of amphiphilic 5-fluoro-2 -deoxyuridylic acid prodrugs. Euro. J. Med. Chem. 40 494-504. 

One of the most well-known examples of effective replacement of hydrogen with fluorine is observed in the antineoplastic drug 5-fluorouracil (Figure 2.1). This compound is metabolized in vivo to 5-fluoro-2 -deoxyuridylic acid (5-fluoro-dUMP), which is the active drug that covalently binds to thymidylate synthase, the enzyme responsible for the essential conversion in DNA synthesis of uridylic acid to thymidylic acid. 

Modifications before the base symbol concern the base, those after the base symbol concern the sugar. Therefore d(fl U) is d(fl U) or poly-5-fluoro-deoxyuridylic acid, but d(Ufl) is d(Ufl) or poly-2 deoxy-2 -fluoro-uridylic acid r(e U) is r(e U) or poly-5-ethyl-uridylic acid, but r(U e) is r(U e) or poly-2 -0-ethyl-ribo-uridylic acid etc. etc. 

Fluorine has the closest atomic dimensions to the hydrogen atom, and pyrimidine analogues where hydrogen is substituted by fluorine are powerful antimetabolites. 5-fluoro-orotic acid (Fig. 12), for instance, prevents the conversion of orotic acid to orotidylic acid (Fig. 2) and the methylation of deoxyuridylic acid to form thymi-dylic acid (Fig. 9). 

It had been known for some time > that FdUMP is an extremely potent inhibitor of thymidylate synthetase, but the nature of inhibition was the topic of considerable controversy. Since the 6-position of 1-sub-stituted 5-fluorouracils is quite susceptible toward nucleophilic attack, it was suspected that FdUMP might exert its inhibitory effect by reaction with the proposed nucleophilic catalyst of thymidylate synthetase. It is now well established that, in the presence of CH,-H4folate, 5-fluoro-2 -deoxyuridylate (FdUMP) behaves as a quasi-substrate for thymidylate synthetase " and is, in effect, an affinity labeling agent for the enzyme. Whereas FdUMP binds relatively poorly to free enzyme, in the presence of the cofactor, CHa-Hifolate, a covalent bond is formed between an amino acid residue of the enzyme and the 6-position of the nucleotide to give the complex depicted in Fig. 1. Although covalent bonds are involved in linking the components of the complex, the reaction is slowly reversible. Nevertheless, the complex is sufficiently stable Ka 10" M) to permit isolation and characterization. 

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