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Last updated date: 19th May 2024
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What are Antimetabolites?

An antimetabolite is a substance that prevents the usage of a metabolite, which is a molecule that occurs naturally in the body's metabolism. Antimetabolites are often structurally identical to the metabolite they interfere with, such as antifolates, which interfere with the usage of folic acid. As a result, competitive inhibition can occur, and the presence of antimetabolites can have harmful effects on cells, such as preventing cell growth and division, making them useful as in cancer treatment.

Some Antimetabolite Drugs are:

  • 5-Fluorouracil 

  • 6-Mercaptopurine 

  • Capecitabine 

  • Cytarabine 

  • Floxuridine

  • Fludarabine

  • Gemcitabine 

  • Hydroxycarbamide

Antimetabolites Mechanism of Action

Let us discuss the antimetabolites mechanism of action, antimetabolites hinder DNA synthesis by acting as fake metabolites that are integrated into the DNA strand or by blocking critical enzymes that limit DNA synthesis. For the S phase, the majority of medicines are cell cycle phase-specific. These medicines work best against quickly cycling cell populations, therefore they're better for fast-growing tumours than slow-growing tumours. The haematopoietic and gastrointestinal systems are the sites of major toxicity. Methotrexate, 5-Fluorourocil, and Cytosine Arabinoside are other examples.

Antimetabolites are a class of anticancer drugs that work by interfering with DNA synthesis to kill cancer cells. 5-fluorouracil (5-FU), capecitabine, floxuridine, cytarabine, gemcitabine, decitabine, and vidaza are some of the most important medications in this class. These compounds are pyrimidine or purine analogues with changed chemical groups that, when incorporated into RNA and DNA, cause cell death during the S phase of cell growth or block enzymes involved in nucleic acid creation. DNA polymerases, thymidylate synthetase, and ribonucleotide reductase are the antimetabolites' principal intracellular targets. Mitosis is prevented and apoptosis is induced in dividing cells when enzymes involved in DNA synthesis are inhibited or antimetabolites are misincorporated into DNA.

Hypomethylating compounds are a type of medication that can help restore normal gene function in cell division and differentiation genes. Hypomethylating drugs may impair cytokine cell signalling and so act as biological response modifiers. 5-azacytidine and Decitabine are two of the antimetabolites that have been found. 

Antimetabolites are linked to coronary vasospasm, which can be caused by endothelial nitric oxide synthase-related direct toxicity on the vascular endothelium or by the endothelium-independent protein kinase C-mediated vasoconstrictive pathway. Direct endothelial injury, which causes microvascular thrombus formation, and disruption of cardiac cellular metabolism are two other pathways considered. ECG observations of ST-segment deviation or inversion, disordered Q waves, and a decrease in QRS amplitude support the myocardial supply-demand mismatch theory.

Category of Antimetabolites on the Basis of Analogues

Antimetabolites are chemicals that prevent RNA or DNA from being synthesised or are integrated into DNA and RNA, resulting in faulty products. Antimetabolites for paediatric cancer are divided into two types:

1. Purine analogues (mercaptopurine and thioguanine) and pyrimidine analogues are structural analogues of stages in nucleotide production (cytarabine, gemcitabine, and fluorouracil).

2. Analogues of important cofactors in nucleotide synthesis, such as methotrexate, a structural analogue of folic acid. Methotrexate blocks the enzyme dihydrofolate reductase, which converts folate to the active tetrahydrofolate form.

Further Classification of Antimetabolite Drugs

The main categories of these drugs include:

Base Analogues (Altered Nucleobases) – Structures that can act as nucleobase substitutes in nucleic acids. This indicates that these molecules are structurally similar enough to the basic components of DNA to be replaced for them. However, because they differ significantly from conventional bases after being incorporated into DNA, the cell's DNA creation is interrupted and it dies.

Purine Analogues – The bigger bases adenosine and guanosine, which are integrated into DNA as adenosine and guanosine, have a similar structure to metabolic purines.

Examples: Azathioprine, Thiopurines, and Fludarabine

Pyrimidine Analogues – It has the same structure as metabolic pyrimidines, the smaller bases like cytosine and thymine that are integrated into DNA.

Examples: 5-Fluorouracil, Gemcitabine, and Cytarabine

Nucleoside Analogues – Alternative nucleosides made up of a nucleic acid analogue and a sugar. This means that these are the same bases as before, but with a sugar group put on top. The base or the sugar component of nucleoside analogues can be changed. They are similar enough to the molecules required to make cellular DNA that they are incorporated into the DNA of the cell but distinct enough that once added to the cell's DNA, they cause the cell to cease growing.

Nucleotide Analogues – Alternatives to nucleotides that include a nucleic acid, a sugar, and 1–3 phosphates. This means that these molecules resemble the bits that make up a cell's DNA and can be incorporated into the DNA of a growing cell. However, because they are analogues and so differ somewhat from ordinary nucleotides, they cause the cell to stop growing and die.

Antifolates – Chemicals that inhibit the activity of folic acid (vitamin B9), which is required for the formation of DNA and the growth of cells.

Types of Chemotherapy

Alkylating Agents

The resting phase of the cell is when alkylating chemicals are most active. These medications have no effect on the cell cycle. Alkylating compounds are employed in chemotherapeutic treatments in a variety of ways:

  • Mustard Gas Derivatives:  Mechlorethamine, Cyclophosphamide, Chlorambucil, Melphalan, and Ifosfamide.

  • Ethylenimines:  Thiotepa and Hexamethylmelamine.

  • Alkyl Sulfonates:  Busulfan.

  • Hydrazines and Triazines: Altretamine, Procarbazine, Dacarbazine and Temozolomide.

  • Nitrosoureas:  Carmustine, Lomustine and Streptozocin.  Nitrosoureas are special in that they can pass the blood-brain barrier, unlike most chemotherapies. They may be beneficial in the treatment of brain tumours.

  • Metal Salts:  Carboplatin, Cisplatin, and Oxaliplatin.

Plant Alkaloids

Plant alkaloids are chemotherapeutic agents generated from specific plant species. The periwinkle (Catharanthus rosea) plant produces vinca alkaloids. The taxanes are manufactured from the Pacific Yew tree's bark (taxus). Antimicrotubule agents include the vinca alkaloids and taxanes. Mayapple podophyllotoxins are generated from this plant. Analogues of camptothecin are obtained from the Asian "Happy Tree" (Camptotheca acuminata). Topoisomerase inhibitors, such as podophyllotoxins and camptothecin analogues, are employed in certain forms of chemotherapy. The alkaloids in plants have a cell-cycle specificity. This means that they assault cells at different stages of division.

  • Vinca Alkaloids: Vincristine, Vinblastine and Vinorelbine.

  • Taxanes:  Paclitaxel and Docetaxel.

  • Podophyllotoxins:  Etoposide and Tenisopide.

  • Camptothecin Analogs: Irinotecan and Topotecan.

Antitumor Antibiotics

Antitumor antibiotics are chemotherapies developed from natural compounds produced by Streptomyces species, a soil fungus. These medications are cell-cycle specific because they function through different phases of the cell cycle. Antitumor antibiotics come in a variety of forms:

  • Anthracyclines: Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, and Idarubicin.

  • Chromomycin:  Dactinomycin and Plicamycin.

  • Miscellaneous:  Mitomycin and Bleomycin.


Antimetabolites are chemotherapeutic treatments that are extremely similar to normal cellular components. When these compounds are incorporated into the cellular metabolism, the cells are unable to divide. Antimetabolites are only active during certain stages of the cell cycle. They assault cells at specific times during the cell cycle. Antimetabolites are categorised based on the chemicals they interact with.

  • Folic Acid Antagonist:  Methotrexate.

  • Pyrimidine Antagonist:  5-Fluorouracil, Floxuridine, Cytarabine, Capecitabine, and Gemcitabine.

  • Purine Antagonist:  6-Mercaptopurine and 6-Thioguanine.

  • Adenosine Deaminase Inhibitor:  Cladribine, Fludarabine, Nelarabine and Pentostatin.

Topoisomerase Inhibitors

Topoisomerase inhibitors are chemotherapy medications that prevent topoisomerase enzymes from working (topoisomerase I and II). Topoisomerase enzymes regulate the alteration of the DNA structure required for replication during chemotherapies.

  • Topoisomerase I Inhibitors:  Irinotecan, topotecan

  • Topoisomerase II Inhibitors:  Amsacrine, etoposide, etoposide phosphate, teniposide

  • Miscellaneous Antineoplastics

  • Several useful types of chemotherapy drugs are unique

  • Ribonucleotide Reductase Inhibitor:  Hydroxyurea. 

  • Adrenocortica Steroid Inhibitor:  Mitotane

  • Enzymes:  Asparaginase and Pegaspargase.

  • Antimicrotubule Agent:  Estramustine

  • Retinoids:  Bexarotene, Isotretinoin, Tretinoin (ATRA)

Aside from the aforementioned methods of chemotherapy, there are many others, including targeted therapy, immunotherapy, and hormone therapy.

Function of Antimetabolites

Cancer Treatment

Antimetabolites can be used to treat cancer because they prevent DNA from being produced, which inhibits cell division and tumour growth. Inhibiting cell division hurts tumour cells more than other cells because cancer cells spend more time dividing than other cells. Antimetabolite medicines are often used to treat leukaemia, breast, ovarian, and gastrointestinal tract cancers, as well as other cancers. Antimetabolite cancer medications are classified as L01B in the Anatomical Therapeutic Chemical Classification System.

Antimetabolites disrupt DNA replication by incorporating chemically altered nucleotides or reducing the availability of deoxynucleotides required for DNA replication and cell growth.

Anti-metabolites imitate purines (azathioprine, mercaptopurine) and pyrimidines, which are the building blocks of DNA. They inhibit these chemicals from being integrated into DNA during the S phase of the cell cycle, effectively preventing normal cell division and development. Anti-metabolites have an impact on RNA production as well. Because thymidine is used in DNA but not RNA (which uses uracil instead), inhibiting thymidine synthesis via thymidylate synthase reduces DNA synthesis but not RNA synthesis.

These medicines are the most extensively used cytostatics due to their effectiveness. Competition for enzyme binding sites involved in critical biosynthetic activities, as well as subsequent integration of these macromolecules into nucleic acids, restricts tumour cell activity and causes apoptosis, or cell death. Most antimetabolites have a high cell cycle selectivity and can target cancer cell DNA replication arrest because of this mode of action.


Antimetabolites can also be antibiotics, such as sulfanilamide medicines, which compete with para-aminobenzoic acid to prevent dihydrofolate production in bacteria (PABA). PABA is required for the creation of folic acid, which works as a coenzyme in the production of purines and pyrimidines, the DNA building blocks. Because mammals can not produce their own folic acid, they are unaffected by PABA inhibitors, which kill bacteria selectively. Antibiotics are not the same as sulfanilamide medicines, which are used to treat infections. Instead, they act by altering the DNA of cancer cells to prevent them from reproducing and developing. Antitumor antibiotics are a type of antimetabolite medication that has no effect on the cell cycle. They work by attaching to DNA molecules and blocking RNA (ribonucleic acid) synthesis, which is a crucial stage in the production of proteins required for cancer cell survival.

Antitumor antibiotics known as anthracyclines work by interfering with enzymes involved in DNA replication during the cell cycle.

Antimetabolites Examples of Anthracyclines Include:

  • Daunorubicin

  • Doxorubicin (Adriamycin)

  • Epirubicin

  • Idarubicin

Antitumor Antibiotics that are Not Anthracyclines Include:

  • Actinomycin-D

  • Bleomycin

  • Mitomycin-C

  • Mitoxantrone

  • Phototrexate

In the treatment of ocular inflammatory illness, antimetabolite agents are useful as corticosteroid-sparing medicines. MMF is helpful for treating disorders in adults and children that have been resistant to previous immunosuppressive medications; it is well tolerated and has few adverse effects. Methotrexate is the most commonly used immunosuppressive drug in children, and it has been shown to be beneficial in treating uveitis caused by juvenile idiopathic arthritis. When compared to other antimetabolite drugs, azathioprine has more severe adverse effects, which limits its use.

Other Uses of Antimetabolites

Antimetabolites, particularly mitomycin C (MMC), are often used as a supplement to trabeculectomy, a surgical treatment for treating glaucoma in the United States and Japan.

Antimetabolites have been found to reduce operative site fibrosis. As a result, its application after external dacryocystorhinostomy, a surgery for treating nasolacrimal duct obstruction, is being studied.

The use of intraoperative antimetabolites such as mitomycin C (MMC) and 5-fluorouracil (5-FU) to treat pterygium is currently being investigated.

Did You Know?

  • An antimetabolite is a substance that competes with, replaces, or inhibits a cell's specific metabolite, interfering with the cell's usual metabolic activity.

  • An antimetabolite is a substance that competes with, replaces, or inhibits a cell's specific metabolite, interfering with the cell's usual metabolic activity.

  • TUMOUR LYSIS SYNDROME is caused by the sudden, rapid death of millions of cells - a particular problem in the successful treatment of patients with leukaemia or lymphoma. TLS results from the development of electrolyte and metabolic disturbances that can produce life-threatening complications, if not managed appropriately.

FAQs on Antimetabolites

1. What is the Role of Antimetabolites?

Answer: Antimetabolites work by imitating or interfering with purines and pyrimidines, which are necessary for DNA synthesis. They are most typically found in cells that are in the S phase of the cell cycle (cell-cycle specific), which is when DNA replication is taking place. Nearly 60 years ago, methotrexate was rationally designed as an antimetabolite to potently block dihydrofolate reductase (DHFR), resulting in brief remissions in juvenile acute leukaemias. 

DHFR regenerates the reduced form of folate, which is required for the production of purines and thymidylate and is deficient in the absence of which leads to inefficient DNA synthesis and replication. Methotrexate has the ability to diffuse directly into cells when given in high concentrations, resulting in substantial toxicity. Nonmalignant cells are likewise harmed by therapy, albeit leucovorin can bypass DHFR and save them. High-dose therapy followed by leucovorin rescue is a typical treatment method for osteosarcoma and hematologic malignancies, especially when the central nervous system is involved.

2. What are the Various Effects of Antimetabolites?

Answer: Myelosuppression and mucositis are side effects of methotrexate. It can also cause renal failure, which can be mitigated by using urine alkalinization. Transaminitis is also visible. Pemetrexed, a new generation antifolate, is an antimetabolite that can help fight lung cancer and mesothelioma. It is thought to influence a number of enzymes, including thymidylate synthase, DHFR, and glycinamide ribonucleotide formyltransferase, all of which contribute to reduced purine and pyrimidine synthesis. To decrease adverse effects, folic acid and vitamin B12 injections are given in conjunction with chemotherapy.