This document summarizes various alkylating agents used to treat cancer. It describes how alkylating agents work by forming covalent bonds with DNA to prevent replication. Specific agents discussed include nitrogen mustard, cyclophosphamide, chlorambucil, melphalan, nitrosoureas like carmustine, alkyl sulfonates like busulfan, ethylenimines like dacarbazine, temozolomide, altretamine, and thiotepa. For many of these, the synthesis and mechanisms of action are outlined. Alkylating agents can cause adverse effects like myelosuppression, sterility, and increased leukemia risk.

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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