7.8.1.3 Antimetabolites
Antimetabolite inhibitors of DNA synthesis act by the competitive or allosteric inhibition
of a number of different enzymes participating in purine or pyrimidine biosynthesis.
Actually, some such compounds interfere with as many as 10–12 different enzymes—
although admittedly to a different degree.
Folic Acid Antagonists.Folic acid antagonists block the biosynthesis of purine
nucleotides. Methotrexate (7.76) is the prototypic folic acid antagonist and functions by
binding to the active catalytic site of dihydrofolate reductase, thereby interfering with the
synthesis of the reduced form that accepts one-carbon units; lack of this cofactor blocks the
synthesis of purine nucleotides. As well as being used in the treatment of cancer, methotrex-
ate has been used in the management of rheumatoid arthritis, psoriasis, and even asthma.
Purine Antimetabolites.Purine synthesis can be blocked by 6-mercaptopurine
(7.77) and 6-thioguanine (7.78). Both require conversion to the mononucleotide in a
“lethal synthesis”—a mechanism distinguished from the formation of suicide substrates
in that the enzyme that transforms the inactive pro-drug to the active inhibitor is different
from the enzyme that is being blocked. Kcatinhibitors are formed and bound by the same
enzyme. Both thiopurines primarily block the amidotransferase in the first step of purine
synthesis as “pseudo-feedback” inhibitors. Additionally, the transformations of inosinic
450 MEDICINAL CHEMISTRY