This document discusses several alkylating agents used to treat cancer: cyclophosphamide, melphalan, chlorambucil, busulfan, and thiotepa. It describes the structures, mechanisms of action, structure-activity relationships, and therapeutic uses of each drug. The key mechanisms involve alkylation of DNA at guanine residues, which causes cross-linking between strands and inhibits processes like replication and transcription, ultimately leading to cell death. The aromatic, chloroethyl, and amino groups influence stability, distribution, and oral availability of the drugs. Collectively, these alkylating agents are used to treat hematological and solid tumors.

1. ALKYLATING AGENTS
By
K. DEVAKI. Pharm.D
Assistant Professor,
Department of Pharmacy Practice,
SREE VIDYANIKETHAN COLLEGE OF PHARMACY.

2. CYCLOPHOSPHOMIDE

3. Structure
CYTOPHOSPHANE
C7H15CL2N2O2P
(RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide

4. MOA

6. In those cells of the body which are having low levels of ALDH,
cyclophosphamide metabolized to phosphoramide mustard.
The metabolite will form cross-linkage between and within the DNA
strands at guanine N-7 positions.
This will finally results into the apoptosis which will lead to the death
of the cell

7. USES
• Cyclophosphamide is used to treat cancer of the ovaries, breast, blood
and lymph system, and nerves (mainly in children).
• Cyclophosphamide is also used for retinoblastoma (a type of eye
cancer mainly in children), multiple myeloma (cancer in the bone
marrow), and mycosis fungoides (tumors on the skin).

8. SAR
•2-chloroethyl group is essential for the activity as the aziridine cation is formed
by this only.
•Aziridine cation will attach with the alkylates of the DNA later.

9. • Aromatic ring introduction will increase the stability of the drug.
• Aromatic ring will further increase the distribution of the drug
throughout the body.
• Benzimidazole ring can provide the local and faster action of the drug.
• Benzimidazole will further decrease the half life of compound

10. Therapeutic Uses
• Treatment of autoimmune diseases
• Treatment of lymphomas, brain cancers, neuroblastoma (cancer that
develops from immature nerve cells), leukemia and solid tumors
• Treatment of AL amyloidosis when given in combination with
thalidomide or lenalidomide and dexamethasone.

11. MELPHALAN

12. Structure
4-[bis(2-Chloroethyl)amino]-L-phenylalani
C13H18Cl2N2O2

13. Mechanism of Action
Alters Guanine nucleotide in DNA through alkylation
Causes linkages between strands of DNA.
DNA and RNA synthesis are inhibited.
Cytotoxicity occurs in both dividing and non-dividing tumors.

15. SAR
• Replacement of the sulfur atom by nitrogen will lower the toxicity.
• 2-chloroethyl group is essential for the activity as the aziridine cation
is formed by this only. Aziridine cation will attach with the alkylates of
the DNA later.
• Binding with the amino group will increase the oral route availability
of the drug
• The introduction of the substituted phenyl group will also increases
the oral route availability of the drug.
• Aromatic ring introduction will increase the stability of the drug.
• Aromatic ring will further increase the distribution of the drug
throughout the body.
• Benzimidazole ring can provide the local and faster action of the
drug.
• Benzimidazol will further decrease the half life of compound.

16. Therapeutic Uses
• Breast cancer
• Neuroblastoma
• Ovarian cancer
• Rhabdomyosarcoma (skeletal muscle tissue)
• Multiple myeloma

17. CHLORAMBUCIL

18. Structure
4-[bis(2-chlorethyl)amino]benzenebutanoic acid
C14H19Cl2NO2

19. Mechanism of Action
Chlorambucil interferes with DNA replication and damages the
cell. It leads to the accumulation of cytosolic p53 which results in
the cell cycle arrest and ultimately the apoptosis.
Chlorambucil shows its effect via three different ways:
1.It alkylates the DNA which leads to the fragmentation of the
DNA by the repair enzymes, and hence, DNA and RNA
synthesis is affected.
2.It can also forms the cross linkages in the DNA which will
interfere with the DNA transcription.
3.It will induce the mispairing of the nucleotides and hence, the
translation activities will be affected.

20. Structural Activity Relationship
• Replacement of the sulfur atom by nitrogen will lower the
toxicity.
• 2-chloroethyl group is essential for the activity as the aziridine
cation is formed by this only. Aziridine cation will attach with the
alkylates of the DNA later.
• Binding with the amino group will increase the oral route
availability o the drug
• The introduction of the substituted phenyl group will also
increases the oral route availability of the drug.

21. Aromatic ring introduction will increase the stability of the drug.
Aromatic ring will further increase the distribution of the drug
throughout the body.
Benzimidazole ring can provide the local and faster action of the
drug.
Benzimidazole will further decrease the half life of compound

22. Therapeutic Uses
• Treatment of chronic lymphocytic leukaemia
• Polycythemia vera
• Trophoblastic neoplasm
• Ovarian carcinoma
• As an immunosuppressive drug for various autoimmune and
inflammatory conditions.

23. BUSULFAN

24. Structure
C6H14O6S2
Butane-1,4-diyl dimethanesulfonate
ALKYL SULFONATE ALKALYTING AGENTS.

25. Mechanism of Action
Busulfan is an alkylating agent that contains 2 labile methanesulfonate
groups attached to opposite ends of a 4-carbon alkyl chain.
Once busulfan is hydrolyzed, the methanesulfonate groups are
released and carbonium ions are produced.
These carbonium ions alkylate DNA, which results in the interference
of DNA replication and RNA transcription, ultimately leading to the
disruption of nucleic acid function.
mechanism of action through alkylation produces guanine-adenine
intra-strand crosslinks.

26. These crosslinks occur through a SN2 reaction guanine N7
nucleophilically attacks the carbon adjacent to the mesylate leaving
group.
This kind of damage cannot be repaired by cellular machinery and
thus the cell undergoes apoptosis.

28. USES
• Chronic myelogenous leukemia ( Decreased WBC
Production Bone Marrow)
• Blood disorders such as polysythemia vera(BLOOD
CANCER) and myeloid metaplasia
• Conditioning regimens prior to bone marrow transplant

29. THIOTEPA

30. Structure
C6H12N3PS
1,1′,1′′-Phosphorothioyltriaziridine

31. Mechanism of Action

32. 1.After administration, thiotepa converts into ethylenimine
groups.
2.Ethylenimine groups attaches with N7 position of guanine
base pair of DNA
This will induce the cross linkages between the ds-DNA.
1.This will further interferes with the processes such as DNA
replication and transcription
2.This will result in the inhibition of the cell growth and apoptosis
of the cell.

33. USES
• Breast cancer
• Ovarian cancer
• Hodgkin’s lymphomas
• Non-Hodgkin’s lymphomas
• Superficial tumors of bladder

34. Thank you