Antimetabolite

An antimetabolite is a chemical with a similar structure to a substance (a metabolite) required for normal biochemical reactions, yet different enough to interfere with the normal functions of cells, including cell division.

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Function

Cancer treatment

Antimetabolites can be used in cancer treatment, as they interfere with DNA production and therefore cell division and the growth of tumors. Because cancer cells spend more time dividing than other cells, inhibiting cell division harms tumor cells more than other cells.

Anti-metabolites masquerade as purine (azathioprine, mercaptopurine) or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the S phase (of the cell cycle), stopping normal development and division.

They also affect RNA synthesis. However, because thymidine is used in DNA but not in RNA (where uracil is used instead), inhibition of thymidine sythesis via thymidylate synthase selectively inhibits DNA synthesis over RNA synthesis.

Due to their efficiency, these drugs are the most widely used cytostatics.

In the ATC system, they are classified under L01B.

Antibiotics

Antimetabolites may also be antibiotics, such as sulfanilamide drugs, which inhibit dihydrofolate synthesis in bacteria by competing with para-aminobenzoic acid.^[1]

Types

Main representatives of these drugs are:

Folic acid analogues

• Methotrexate, a folic acid analogue, prevents the formation of tetrahydrofolate, essential for purine and pyrimidine synthesis, by inhibiting dihydrofolate reductase. This leads to inhibited production of DNA, RNA and proteins (as tetrahydrofolate is also involved in the synthesis of amino acids serine and methionine).

Purine analogues

• Azathioprine is the main immunosuppressive cytotoxic substance. It is widely used in transplantations to control rejection reactions. It is nonenzymatically cleaved to 6-mercaptopurine that acts as a purine analogue and an inhibitor of DNA synthesis. By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity. It also successfully suppresses autoimmunity.
• Mercaptopurine
• Thioguanine is used to treat acute leukemias and induction of remissions in acute granulocytic leukemias
• Fludarabine inhibits function of multiple DNA polymerases, DNA primase, DNA ligase I and is S phase-specific (since these enzymes are highly active during DNA replication).
• Pentostatin and cladribine are adenosine analogs which are primarily used to treat Hairy cell leukemia.

Pyrimidine analogues

• 5-fluorouracil (5FU) which inhibits thymidylate synthase.
• Floxuridine (FUDR)
• Cytosine arabinoside

See also

• Base analog

References

1. ^ "The Organic Chemistry of Drug Design and Drug Action" (2nd edition), R. B. Silverman, 2004.