Synthesis of Alkylating agents

1. Synthesis of Alkylating Agents
SAKSHAM PALAWAT
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2. INTRODUCTION
Cancer:
It is defined as a disease characterized by uncontrolled proliferation
of cell division and multiplication of own body’s cell.
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3. Alkylating agents
• Alkylating agents are the compounds that have groups which form
covalent bond with the cell substituents.
• A carbonium ion is a reactive intermediate.
• Most have two alkylating groups and can cross link two nucleophilic sites
(mainly at N7 position of guanine) in the DNA.
• Cross linking prevents DNA replication through pairing of alkyl guanine
• Can also cause excision of guanine and chain breakage.
Adverse effects: it includes –
• Myelosuppression
• Sterility
• increased risk of acute non lymphocytic leukemia
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4. Alkylating Agents
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6. Nitrogen Mustard
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7. Mechlorethamine
Synthesis:
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8. Ifosfamide
Synthesis:
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9. Cyclophosphamide
Synthesis:
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10. Metabolism of Cyclophosphamide
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11. Chlorambucil
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12. Prodrug Approach of Chlorambucil
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13. Melphalan
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14. Mechanism
If aromatic ring is attached to alkylating side chain
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15. Nitrosoureas
• Mainly lipid soluble and can cross blood brain barrier
• Mostly used in the treatment of tumor in brain and in meninges
• Cause bone marrow depression
• Act as alkylating agent via formation of Aziridinium ring formation
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16. Carmustine
Synthesis:
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17. Lomustine
Synthesis:
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18. Semustine
Synthesis:
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19. Estramustine
Synthesis:
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20. Alkyl Sulfonates
• Esters of alkane sulfonic acids with the general formula R-SO2-O-R‘
• leads to the misreading of the DNA codes, single-strand breaks, and cross-
-linking of DNA.
• Used to treat chronic myelogenous leukemia (CML).
• Also lead to discoloration of the skin, especially of the hands and nails,
rashes and itching.
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21. Busulfan
Synthesis:
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22. Ethylenimines
• used as an adjuvant to radiation therapy of retinoblastoma and injected
into the carotid artery
• used in the palliative treatment of malignant neoplasm's
• Also used in the treatment of carcinoma of breast, ovaries, colon-rectum
and rectum.
• It is found useful in the treatment of malignant lymphomas and
bronchogenic carcinomas.
• The ‘drug’ also crosses the blood-brain barrier (BBB).
• It has been observed that it undergoes absorption through serous
membranes, bladder and pleura, to a certain degree.
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23. Dacarbazine
Synthesis:
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24. Limitation – cause Photolysis
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25. Temozolomide
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• It is an imidazotetrazine derivatives
• It is antitumor drug that is capable of entering the central nervous system and
used to treat malignant brain tumor.
• Act as a as a second-line treatment for astrocytoma and a first-line treatment
for Glioblastoma multiforme.

26. Synthesis of Temozolomide
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27. Altretamine
Synthesis:
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28. Thiotepa
Synthesis:
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29. References
(1) Robert A. Weinberg. How Cancer Arises ,An Explosion of Research is Uncovering the Long- Hidden
Molecular Underpinnings of Cancer-and Suggesting New Therapies. Sci. Am. 1996, 62–68.
(2) Beale, J. M.; John H. Block. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical
Chemistry, 12th Editi.; David B. Troy, Ed.; Wolters Kluwer health, 2011.
(3) Myles, A.; Penselau, C.; Friedman, O. M. Synthesis of Aldophosphamide, A Key Cyclophosphamide
Metabolites. Tetrahedron Lett. 1977, No. 29, 2475–2478.
(4) Alagarsamy, V. Textbook of Medicinal Chemistry, Volume II; 2010.
(5) Singh, R. K.; Prasad, D. N.; Bhardwaj, T. R. Design, Synthesis, Chemical and Biological Evaluation of
Brain Targeted Alkylating Agent Using Reversible Redox Prodrug Approach. Arab. J. Chem. 2017, 10
(3), 420–429.
(6) Ashutosh Kar. Medicinal Chemistry, fourth.; New Age International (P) Ltd.: New Delhi- 110002,
2007.
(7) Iradyan, M. A.; Iradyan, N. S.; Stepanyan, G. M.; Arsenyan, F. G.; Garibdzhanyan, B. T. Antitumor
Activity of Imidazole Derivatives: Dacarbazine and the New Alkylating Agent Imidazene (Review).
Pharm. Chem. J. 2010, 44 (4), 175–182.
(8) Wanner, M. J.; Koomen, G.-J. A New Synthesis of Temozolomide. J. Chem. Soc. Perkin Trans. 1 2002,
4 (16), 1877–1880.
(9) Chand, M.; Shukla, A. Novel Synthesis of Altretamine and Their Process Impurities Using
Imidazolium Type of Ionic Liquids. 1–9.
(10) https://www.cancer.gov/about-cancer/understanding/what-is-cancer/types of cancer
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30. Thank You!
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