Antimetabolites

Antimetabolites are a class of drugs and chemical agents that resemble naturally occurring metabolites and disrupt nucleotide synthesis or function. They are used primarily in cancer therapy and to a lesser extent in autoimmune diseases. Most antimetabolites are purine or pyrimidine analogs that interfere with DNA or RNA synthesis during the S phase of the cell cycle.

Common examples include methotrexate, 5-fluorouracil, cytarabine, gemcitabine, mercaptopurine and azathioprine. Methotrexate inhibits dihydrofolate reductase, lowering levels of tetrahydrofolate and thereby reducing thymidine and purine production. 5-fluorouracil is converted to a metabolite that inhibits thymidylate synthase, depleting thymidine pools. Cytarabine and gemcitabine are cytidine analogs that become incorporated into DNA and interfere with polymerases and chain elongation. Purine analogs such as mercaptopurine and its prodrug azathioprine perturb de novo purine synthesis and can be misincorporated into nucleic acids.

They are widely employed in chemotherapy regimens for leukemias, lymphomas and solid tumors, as well as in autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. Side effects commonly include myelosuppression, mucositis, hepatotoxicity and gastrointestinal symptoms; nephrotoxicity may occur with some agents. Resistance can arise through reduced drug activation, increased target enzyme activity, altered drug transport, or enhanced salvage pathways.

These agents remain central to modern oncology and immunosuppressive therapy, often used in combination with other modalities.