The drugmethotrexate (bottom) is an antimetabolite that interferes with the metabolism offolic acid (top)
Anantimetabolite is a chemical thatinhibits the use of ametabolite, which is another chemical that is part of normalmetabolism.[1] Such substances are often similar in structure to the metabolite that they interfere with, such as theantifolates that interfere with the use offolic acid; thus,competitive inhibition can occur, and the presence of antimetabolites can havetoxic effects on cells, such as haltingcell growth andcell division, so these compounds are used inchemotherapy for cancer.[2]
Antimetabolites can be used incancer treatment,[3] as they interfere with DNA production and therefore cell division and tumor growth. Because cancer cells spend more time dividing than other cells, inhibiting cell division harms tumor cells more than other cells. Antimetabolite drugs are commonly used to treat leukemia, cancers of the breast, ovary, and the gastrointestinal tract, as well as other types of cancers.[4] In theAnatomical Therapeutic Chemical Classification System antimetabolite cancer drugs are classified under L01B.
Antimetabolites generally impair DNA replication machinery, either by incorporation of chemically altered nucleotides or by depleting the supply of deoxynucleotides needed for DNA replication and cell proliferation.
Examples of cancer drug antimetabolites include, but are not limited to the following:
Anti-metabolites masquerade as apurine (azathioprine,mercaptopurine) or apyrimidine, chemicals that become the building-blocks of DNA. They prevent these substances from becoming incorporated into DNA during theS phase (of thecell cycle), stopping normal development and cell division.[6] Anti-metabolites also affect RNA synthesis. However, becausethymidine is used in DNA but not in RNA (whereuracil is used instead), inhibition of thymidine synthesis viathymidylate synthase selectively inhibits DNA synthesis over RNA synthesis.
Due to their efficiency, these drugs are the most widely usedcytostatics. Competition for the binding sites ofenzymes that participate in essential biosynthetic processes and subsequent incorporation of these biomolecules intonucleic acids, inhibits their normal tumor cell function and triggersapoptosis, the cell death process. Because of this mode of action, most antimetabolites have high cell cycle specificity and can target arrest of cancer cell DNA replication.[7]
Anthracyclines are anti-tumor antibiotics that interfere with enzymes involved in copying DNA during thecell cycle.[4] These represent an alternative mode of cancer treatment, blocking tumour growth through non-mimetic mechanisms such as DNA intercalation or inducing damage to nucleic acids.
Some antimetabolites can also beantibiotics, such assulfanilamide drugs, which inhibitdihydrofolate synthesis in bacteria by competing withpara-aminobenzoic acid (PABA).[9] PABA is needed in enzymatic reactions that produce folic acid, which acts as a coenzyme in the synthesis of purines and pyrimidines, the building-blocks of DNA. Mammals do not synthesize their own folic acid so they are unaffected by PABA inhibitors, which selectively kill bacteria.
Antimetabolites, particularlymitomycin C (MMC), are commonly used in America and Japan as an addition totrabeculectomy, a surgical procedure to treatglaucoma.[10]
Intraoperative antimetabolite application, namelymitomycin C (MMC) and5-fluorouracil (5-FU), is currently being tested for its effectiveness of managingpterygium.[12]
base analogues (alterednucleobases) – structures that can substitute for a normalnucleobases innucleic acids. This means that these molecules are structurally similar enough to the basic components of DNA that they can be substituted in. However, since they are slightly different from the normal bases after they are incorporated into the DNA, the DNA production is halted and the cell dies.
nucleoside analogues –nucleoside alternatives that consist of anucleic acid analogue and asugar. This means these are the same bases as above, but with an added sugar group. For the nucleoside analogues either the base or the sugar component can be altered. They are similar enough to the molecules used to build cellular DNA that they are incorporated by the cell into its DNA, but different enough that after being added the cell's DNA they stop cell growth.
nucleotide analogues –nucleotides alternatives that consist of anucleic acid, asugar, and 1–3phosphates. This means these molecules look exactly like the pieces used to build DNA in a cell and can be incorporated into a growing cell's DNA. However, because they are analogues and therefore slightly different from regular nucleotides, causing the cell's growth to be halted and the cell to die.
antifolates – chemicals that block the actions offolic acid (vitamin B9) which is needed to build DNA and allow cells to grow.
^Smith AL (1997).Oxford dictionary of biochemistry and molecular biology. Oxford [Oxfordshire]: Oxford University Press. p. 43.ISBN978-0-19-854768-6.
^Peters GJ, van der Wilt CL, van Moorsel CJ, Kroep JR, Bergman AM, Ackland SP (2000). "Basis for effective combination cancer chemotherapy with antimetabolites".Pharmacology & Therapeutics.87 (2–3):227–253.doi:10.1016/S0163-7258(00)00086-3.PMID11008002.
^abMatera C, Gomila AM, Camarero N, Libergoli M, Soler C, Gorostiza P (November 2018). "Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy".Journal of the American Chemical Society.140 (46):15764–15773.doi:10.1021/jacs.8b08249.hdl:2445/126377.PMID30346152.S2CID53043366.
^Avendano C, Menendez CJ (2015).Medicinal Chemistry of Anticancer Drugs (2nd ed.). Elsevier Science.
^Mashita T, Kowada T, Takahashi H, Matsui T, Mizukami S (June 2019). "Light-Wavelength-Based Quantitative Control of Dihydrofolate Reductase Activity by Using a Photochromic Isostere of an Inhibitor".ChemBioChem.20 (11):1382–1386.doi:10.1002/cbic.201800816.PMID30656808.S2CID58567138.
^Silverman RB (2004).The Organic Chemistry of Drug Design and Drug Action (2nd ed.).
