Synthesis of Alkylating agents

Synthesis of Alkylating agents

1. Synthesis of Alkylating Agents SAKSHAM PALAWAT 1

2. INTRODUCTION Cancer : It is defined as a disease characterized by uncontrolled proliferation of cell division and multiplication of own body’s cell. 2

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 3

4. Alkylating Agents 4

5. 5

6. Nitrogen Mustard 6

7. Mechlorethamine Synthesis: 7

8. Ifosfamide Synthesis: 8

9. Cyclophosphamide Synthesis: 9

10. Metabolism of Cyclophosphamide 10

11. Chlorambucil 11

12. Prodrug Approach of Chlorambucil 12

13. Melphalan 13

14. Mechanism If aromatic ring is attached to alkylating side chain 14

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 15

16. Carmustine Synthesis: 16

17. Lomustine Synthesis: 17

18. Semustine Synthesis: 18

19. Estramustine Synthesis: 19

20. Alkyl Sulfonates Esters of alkane sulfonic acids with the general formula R-SO 2 -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. 20

21. Busulfan Synthesis:   21

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 . 22

23. Dacarbazine Synthesis: 23

24. Limitation – cause Photolysis 24

25. Temozolomide 25 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 26

27. Altretamine Synthesis: 27

28. Thiotepa Synthesis: 28

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 29

30. Thank You! 30