acid to AMP and GMP are also inhibited. Both 6-mercaptopurine and 6-thioguanine
have been used in the treatment of acute leukemia. Both compounds are easily prepared;
for example, 6-thioguanine is readily prepared by treating guanine with phosphorus
pentasulfide in pyridine. Fludarabine phosphate (7.79, 2-fluoro-arabinofuranosyladenine
monophosphate)and cladribine (7.80, 2-chlorodeoxyadenosine) are other compounds
that function as purine antimetabolites.
Pyrimidine Antimetabolites. The commonly used drug fluorouracil (7.81, 5-FU) is
the prototype pyrimidine antimetabolite. 5-FU undergoes biotransformation to ribosyl
nucleotide metabolites, including 5-fluoro-2′-deoxyuridine-5′-phosphate (FdUMP)
which in turn forms a covalent bond to the complex formed by the thymidylate synthase
enzyme and its N5,10-methylenetetrahydrofolate cofactor; this inhibits the synthesis of
thymine nucleotides and terminates DNA synthesis by the process of “thymineless
death.” Traditionally, this compound is prepared by condensing S-ethylisothiouronium
bromide with the potassium salt (enolate) of ethyl-2-fluoro-2-formylacetate.
Capecitabine (7.82) is a fluoropyrimidine carbamate prodrug that is converted to 5-FU.
In another pyrimidine antimetabolite, cytarabine (7.83, Ara-C, 1-β-D-arabofuranosyl-
cytosine), the ribose moiety of cytidine is replaced by the epimeric arabinose. This drug
inhibits DNA polymerases after its bioconversion to ara-CTP, competing with CTP. The
adenine analog Ara-A acts in a similar fashion. Both drugs are used in leukemia only;
they are inactive against solid tumors.
ENDOGENOUS CELLULAR STRUCTURES 451