The document discusses antimetabolites, a class of drugs used in cancer chemotherapy that interfere with DNA synthesis by targeting enzymes. It classifies them into folate, purine, and pyrimidine antagonists, detailing specific drugs like methotrexate, 6-mercaptopurine, and 5-fluorouracil, along with their mechanisms and clinical applications. The overview highlights how these drugs affect rapidly dividing cancer cells while potentially causing side effects such as leukopenia and anemia.

1. ANTIMETABOLITES
PRESENTER- DR SABA RAZZAK
PHARMACEUTICAL CHEMISTRY

2. OUTLINES
• CANCER
• CHEMOTHERAPEUTIC AGENTS
• MECHANISM OF ACTION
• INTRODUCTION TO ANTIMETABOLITES
• CLASSIFICATION
• FOLATE ANTAGONIST
• PURINE ANTAGONIST
• PYRIMIDINE ANTAGONIST
• CONCLUSION

3. CANCER
• Cancer, also called malignancy, is an abnormal growth of cells.
• There are more than 100 types of cancer, including breast cancer, skin cancer,
lung cancer, colon cancer, prostate cancer, and lymphoma.
• Symptoms vary depending on the type.
• Cancer treatment may include chemotherapy, radiation, and/or surgery.

6. ANTIMETABOLITES

7. INTRODUCTION- ANTIMETABOLITES
• Antimetabolites are drugs that interfere with one or more enzymes or their
reactions that are necessary for DNA synthesis.
• These are the drugs used in cancer chemotherapy.
• Cancer cells divide more rapidly compared to normal cells so antimetabolites
affect cancer cell replication more than they affect normal cell replication.
• Generally, antimetabolites induce cell death during the S phase of cell
growth when incorporated into RNA and DNA or inhibit enzymes needed for
nucleic acid production.

8. CLASSIFICATION- ANTIMETABOLITES
FOLATE ANTAGONIST METHOTREXATE (MTX)
PURINE ANTAGONIST 6-MERCAPTOPURINE(6-MP), 6-
THIOGUANINE(6-TG),
AZATHIOPURINE
PYRIMIDINE ANTAGONIST 5-FLOUROURACIL(5-FU),
CAPECITABINE, CYTRABINE

9. FOLATE ANTAGONIST
 METHOTREXATE (MTX)
METHOTREXATE

10. • Folic acid is a necessary compound for the production of nucleotides.
• It was empirically observed in patients with leukemia that diets low in folate
produced lower white cell counts than observed in leukemic patients on normal
folate diets.
• In 1948, a folate antagonist was found effective in childhood leukemia.
• The antifolate medication METHOTREXATE became an early chemotherapy drug.
INTRODUCTION- FOLATE ANTAGONIST

11. • Intracellulary (between cells) folate is converted by the enzyme dihydrofolate
reductase (DHFR) to dihydrofolate. This compound is then reduced to
tetrahydrofolate (THDF). THDF acts as a carbon carrier compound that donates
methyl groups to end target molecules through the enzymatic action of thymidine
synthetase.
• DHFR is the site where the folate antagonists function, hence interfere with
nucleotide formation.
MECHANISM OF ACTION- FOLATE ANTAGONIST

12. FOLIC ACID AND METHOTREXATE
Methotrexate (4-amino-N methyl pteroylglutamic acid) is structurally similar to folic acid,
the natural substrate for target enzyme DHFR, differ from folic acid in only two areas

13. METHOTREXATE (MTX)
Methotrexate is an antimetabolite with anti-inflammatory and immunosuppressant
effect.
It binds to DHFR reversibly and inactivates it. This prevents methylation and
decreases available supplies of purine and thymidine bases for new DNA and RNA
synthesis, thus inhibits cellular replication. It is active in the S phase of cell growth.
USE- for treating various neoplasms, leukemia, osteosarcoma, rheumatoid
arthritis, psoriasis, breast cancer, head and neck cancer.

14. PURINE ANTAGONIST
 6-MERCAPTOPURINE

15. • Purine antagonists stop synthesis by decreasing the production of the purine
bases or that the antagonist molecules themselves incorporated into the DNA
strands during synthesis and halt cell replication.
• Without adequate amounts of the purine bases, nucleotide production stops and
the cancer cell dies.
PURINE ANTAGONIST

16. • IUPAC name - 3,7-dihydropurine-6-thione
• C5H4N4S
• 6-Mercaptopurine (6-MP) is a purine agent.
• Active in the S phase of cell proliferation. When it is incorporated into DNA and RNA,
the nucleic acids are rendered useless.
• 6-MP may also act through inhibition of de novo synthesis of the purine bases.
• Genetic mutation may lead to purine resistance.
• USE - Against acute lymphocytic leukemia.
6-MERCAPTOPURINE

17. PYRIMIDINE ANTAGONIST
 5-flurouracil (5-FU)
Pyrimidine

18. • Duschinsky synthesized and Heidelberger, in 1957, introduced 5-flurouracil (5-
FU).
• CHEMISTRY - 5-FU is a pyrimidine base containing a fluoride atom at the 5
carbon position on the ring.
PYRIMIDINE ANTAGONIST

19. • Uracil is a naturally occurring pyrimidine base used in nucleic acid synthesis. It is converted
to thymidine by enzyme action.
• 5-FU is similar in structure to uracil and is converted to two active metabolites (FdUMP and
FUTP) that inhibit the activity of the enzyme thymidylate synthetase. The enzyme normally
converts uracil to thymidine by adding a methyl group at the fifth carbon of the pyrimidine
ring.
• 5-FU mimics the natural base and functions to inhibit DNA synthesis.
MECHANISM OF ACTION- 5-FLUOROURACIL

21.  The purine, pyrimidine, and folate antagonists represent a second group of cytotoxic drugs
active against rapidly dividing or metabolizing cells.
 Included among these are the purine antagonists 6-mercaptopurine, the pyrimidine antagonist
fluorouracil, and the folate antagonist methotrexate.
 These agents are given with, or within 48 hours of antigen administration and inhibit cellular
proliferation and initial differentiation, usually through inhibition of DNA or RNA synthesis.
 They all seem to impair CMI and humoral immunity.
 Originally developed for cancer therapy, these drugs can affect any group of rapidly proliferating
cells.
 Because they are particularly toxic to hematopoietic tissues, they may induce leukopenia
(especially neutropenia), thrombocytopenia, and anemia.
CONCLUSION - ANTIMETABOLITES