ALKYLATING AGENT. antineoplastic agentspptx

Medicinal chemistry- Antineoplastic Agents-ALKYLATING Agents
description regarding the Structure-Activity Relationship of alkylating agents, mechanism of action of alkylating agents and its uses

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

5. 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

6. 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).

7. 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.

8. 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

9. 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 .

10. MELPHALAN

11. Structure 4-[bis(2-Chloroethyl)amino]-L-phenylalanine C13H18Cl2N2O2

12. 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.

13. 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.

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

15. CHLORAMBUCIL

16. Structure 4-[bis(2-chlorethyl)amino]benzenebutanoic acid C 14 H 19 Cl 2 NO 2

17. 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: It alkylates the DNA which leads to the fragmentation of the DNA by the repair enzymes, and hence, DNA and RNA synthesis is affected. It can also forms the cross linkages in the DNA which will interfere with the DNA transcription. It will induce the mispairing of the nucleotides and hence, the translation activities will be affected.

18. 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.

19. 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

20. Therapeutic Uses Treatment of chronic lymphocytic leukaemia P olycythemia vera Trophoblastic neoplasm Ovarian carcinoma As an immunosuppressive drug for various autoimmune and inflammatory conditions.

21. BUSULFAN

22. Structure C 6 H 14 O 6 S 2 Butane-1,4-diyl dimethanesulfonate ALKYL SULFONATE ALKALYTING AGENTS.

23. 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.

24. 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 .

25. 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

26. THIOTEPA

27. Structure  C 6 H 12 N 3 PS 1,1′,1′′-Phosphorothioyltriaziridine

28. Mechanism of Action

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

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

31. Thank you