Shortened description of STATURAL ACTIVITY RELATIONSHIP OF ANTIMETABOLITES & its MECHANISM OF ACTION - ANTINEOPLASTIC AGENTS (folate antagonist, purine antagonist & pyridine antagonist)(MEDICINAL CHEMISTRY) quite useful for B PHARMACY & Pharm D Students.

1. ANTIMETABOLITES
Dr. K. Devaki, Pharm.D
Asst. Professor,
Department of Pharmacy
Practice

4. THIOGUANINE

5. STRUCTURE
C5H5N5S
2-amino-purine-6(7H)-thione

6. MOA

7. Uses
• This drug is given for the treatment of acute myelogenous leukemia
(A type of cancer of the blood and bone marrow with excess immature
white blood cells).

8. 6-MERCAPTOPURINE

9. STRUCTURE
C5H4N4S
6-MERCAPTOPURINE
3,7-dihydropurine-6-thione

10. MOA
• Mercaptopurine competes with hypoxanthine and guanine
which are purine derived structures, for the HGPRT
(Hypoxanthine-guanine phosphoribosyl transferase enzyme].
Mercaptopurine is then converts into Thio Inosin
Monophosphate.
• Thio inosine monophosphate (TIMP) inhibits conversion of
inosinic acid to xanthylic acid and adenylic acid through adenyl
succinate.
• Methylation of thio inosine monophosphate forms 6-
methylthioinosinate (MTIMP).

11. Glutamine-5-phosphoribosylpyrophosphate amidotransferase is
the enzyme requires for the purine ribonuceoltide synthesis. This
enzyme is inhibited by Thio Inosine Monophosphate and MTIMP.
Since, Glutamine-5-phosphoribosylpyrophosphate
aminotransferase is rate limiting factor for purine synthesis, this
inhibits the synthesis and functioning of the RNA and DNA.
Thus, 6-Mercaptopurine interferes with synthesis of glycoprotiens
and interconversion of nucleotides.

12. Guanosine monophosphate synthetase

13. SYNTHESIS
SODIUM THIOCYANATE
METHOD 1

14. METHOD 2
Potassium
Hydrosulfide

15. SAR
• The activity of the drug increases with increase in
the carbon chain up-to 15-16 carbons, after that,
it again decreases.
• Substituent at position 6 which can lead to the
increase in the resonance at 6th position will lead
to increase in the activity of the drug.

16. Introduction of the hydrophobic substituent at
6th position (THIONE )will increase the activity of
the drug.
Substitutions at 2nd position may not change the
activity of the drug, or it may decrease the activity
of the drug depending upon the type of substituent.

17. Therapeutic uses
• Acute lymphoblastic leukemia
• Ulcerative colitis
• Crohn’s disease

18. AZATHIOPRINE
Purine antagonist

19. STRUCTURE
6-[(1-Methyl-4-nitro-1H-imidazol-5-
yl)sulfanyl]-7H-purine
C9H7N7O2S

20. SAR SIMILAR TO THE 6-MERCAPTOPURINE

21. MOA
Azathioprine inhibits the synthesis of purine in the cell.
This will further leads to the inhibition of synthesis of DNA and
RNA.
Azathioprine also interacts with cellular metabolism and results
in the inhibition of mitosis.

22. Therapeutic Uses
• Used as an immunosuppressive agent for prevention of
rejection of the transplanted organs.
It is given for the Treatment of
• Autoimmune diseases
• Rheumatoid arthritis
• Pemphigus [a rare skin DIS].
• Autoimmune hepatitis
• Myasthenia gravis
• As a steroid sparing agent for inflammatory bowel diseases.

23. FLUROURACIL
PYRIDINE ANTAGONIST

24. STRUCTURE
5-Fluoro-1H,3H-pyrimidine-2,4-dione
C4H3FN2O2
Y

25. Normal PYRIDINE
FLUROURACIL

26. MOA
5-Fluororacil binds with thymidylate synthase enzyme to form a ternary complex
system.
Formation of thymidylate form uracil is inhibited due to the complex formation.
 The drug can also get inserted in the place of UTP (Uridine triphosphate) in the
RNA, which result in the inhibition of the protein synthesis in the cell.
 This overall mechanism leads o the death of the cell.

27. • The molar refractivity of the Y substituent will produce increase
in the activity of drug.
• Substituent at Y with (CH2)3NRiR2 with R2 = COCH3,
COC6H5, or COOCeH5 will produce a negative effect on the
activity of the drug.
• SH at 4th position will increase the activity of drug.
• Substituent which are bulky in nature at Y position will produce
negative effect on activity.
• Electron withdrawing groups at 5th position will increase the
activity of drug.
SAR

28. Therapeutic Uses
• Colon anal and rectal cancer
• Breast cancer
• GIT cancers
• Bladder and Hepatobiliary cancer
• Cervical cancer
• Thymic cancer
• Squamous cell and neuroendocrine tumors.

29. FLOXURIDINE
PYRIDINE ANTAGONIST

30. • C9H11FN2O5
• 5-Fluoro-1-[4-hydroxy-5-
(hydroxymethyl) hydrofuran-2-
yl]-1H-pyrimidine-2,4-dione
STRUCTURE

31. FLOXURIDI
NE

32. Therapeutic uses
Floxuridine is used to treat cancer of gastrointestinal (GI) tract
(cancer of the stomach or intestines) that has spread to the
live

33. Cytarabine
PYRIDINE ANTAGONIST

34. • 4-amino-1-[(3,4-dihydroxy-5-
(hydroxymethyl)oxolan-2-yl]
pyrimidin-2-one
STRUCTURE

35. MOA
• Cytarabine gets converted into active form cytarabine
triphosphate by the action of deoxycytidine kinase within the
cell.
• ii. Competition of cytarabine triphosphate for the DNA
polymerase enzyme inhibits the synthesis of DNA.
• iii. Further, the drug produces cytotoxicity in the cell through
incorporation into DNA and RNA.
• iv. Cytarabine produces its effects mainly on the cell which are
actively dividing by blocking the progression of the cell from G-1
phase to the S phase.
• v. These overall results in the death of the actively dividing
cells.

36. •SAR SIMILAR TO THE FLUROURACIL

37. Therapeutic Uses
• Acute & Chronic mylogenous leukemia
• Acute lymphocytic leukemia
• Acute promyelocytic leukemia (immature white blood cells
called promyelocytes accumulate in the bone marrow).
• Hodgkin’s lymphoma
• Meningeal leukemia
• Cancers found in the lining of brain and spinal cord

38. METHOTREXATE
Folate antagonist

39. C20H22N8O5
(4-{[(2,4-Diaminopteridin-6-
yl)methyl](methyl)amino}benzo
yl)amino] petanedioic acid
STRUCTURE
Glutamate tail
1
4

40. Mechanism of Action
• i. Methotrexate competitively inhibits dihydrofolate reductase.
• ii. The synthesis of tetrahydrofolate decreases.
• iii. Due to this, the synthesis of nucleoside thymidine also decreases.
• iv. This inhibits the synthesis of DNA.
• v. Further, the purine synthesis is also inhibited by the methotrexate
as the tetrahydrofolate is important for the synthesis of purine also.

41. SAR
• Replacement of glutamate tail with lipophillic agents can increase the
transportation of the drug through folate carrier system.
• Thiourea entity can increase the activity of the drug
• Replacement of Thiazole with imidazol will increase the activity of the
drug.
• Tetrahydroquinazolines derivatives will affect the ligand-enzyme
interaction in a positive manner, where the dibenzodiazepine ring will
show the pharmacophoric features which are essential for the
activity of the drug.

42. • Substitution at 2nd, 3rd and 6th positions in the quinazolinone
nucleus will inhibit the action of the drug.
• Substitution at ortho and para positions in phenyl ring will
decrease the tendency of the drug to bind with DHFR, thus
decreasing the activity of the drug.
• Combining the drug with copper metal can also increase the
activity of the drug.

43. SYNTHESIS
• Condensation of 2,3-dibromopropionaldehyde with 2,4,5,6-
tetraaminopyrimidine to produce 6-bromomethyl-2,4-
diaminopteridine.
• ii. 6-bromomethyl-2,4-diaminopteridine will undergo further
condensation with N-(para-(methylamino)benzoyl)glutamic acid.
This will lead to the synthesis of methotrexate.

46. THERAPEUTIC USES
• Acute lymphoblastic leukemia
• Polyarticular juvenile idiopathic arthritis.
• Recalcitrant
• Disabling psoriasis
• Estational choriocarcinoma
• Chorioadenoma destruens
• Hydatiform mole
• Breast cancer
• Epidermoid cancer of the head and neck
• Advanced mycosis fungoides
• Lung cancer
• Advanced non-hodgkin’s lymphoma
• Acute lymphocytic leukemia.

47. END