1. Patrick: An Introduction to Medicinal Chemistry 5e
Chapter 21
ANTICANCER AGENTS
ALKYLATING AND
METALLATING AGENTS
Titles modified

2. Alkylating agents Notes Contain highly electrophilic groups
Form covalent bonds to nucleophilic groups in DNA (e.g. 7-N of guanine)
Prevent replication and transcription
Useful anti-tumour agents
Toxic side effects (e.g. alkylation of proteins)
Used as anticancer agents
Can cause interstrand and intrastrand crosslinking if two electrophilic groups are present
Alkylation of nucleic acid bases can result in miscoding
crosslinking

3. Alkylating agents Crosslinking Intrastrand crosslinking
Interstrand crosslinking
Cfrodsdlinking
Red blobs

4. Alkylating agents Nucleophilic groups on nucleic acid bases Cytosine
Guanine
Adenine

5. Alkylating agents
Miscoding resulting from alkylated nucleic acid bases
Cytosine
Guanine
Guanine prefers
keto tautomer
Normal base pairing
Alkylated guanine prefers enol tautomer
Abnormal base pairing

6. Alkylating agents Chlormethine Notes Used medicinally in 1942
Example of a nitrogen mustard
Causes intrastrand and interstrand crosslinking
Prevents replication
Monalkylation of guanine also possible
Analogues with better properties have been prepared
Crosslinking
Methly grouop

7. Alkylating agents Chlormethine Mechanism of action Crosslinked DNA
Mechlorethamine
Aziridine ion
Crosslinked DNA

8. Alkylating agents Chlormethine analogues
Aromatic ring is electron withdrawing
Lowers nucleophilic strength of nitrogen
Less reactive alkylating agent
Less side reactions and less toxic
Melphalan
Aromatic ring is present
Less reactive alkylating agent
Mimics phenylalanine
Transported into cells by transport proteins
Electron withdrawing
Uracil mustard
Uracil ring is electron withdrawing
Less reactive alkylating agent
Mimics a nucleic acid base
Concentrated in fast growing cells

9. Alkylating agents Chlormethine analogues
Estramustine
Urethane group is electron withdrawing
Lowers nucleophilic strength of nitrogen
Alkylating group is attached to estradiol
Steroid is hydrophobic
Capable of crossing cell membranes
Urethane
Electron withdrawing
estradiol

10. Alkylating agents Cyclophosphamide Notes
Cytochrome P450 enzymes
Cyclophosphamide
Alkylating agent
Acrolein
Curly arrows
Notes
Cyclophosphamide is the most commonly used alkylating agent
Non-toxic prodrug
Orally active
Acrolein is associated with toxicity

11. Alkylating agents Nitrosoureas Notes
Decompose in the body to form an alkylating agent and a carbamoylating agent
Curly arrows

12. Alkylating agents Nitrosoureas Notes
Alkylating agent causes interstrand crosslinking
Cross linking between G-G or G-C
Carbamoylating agent reacts with lysine residues on proteins
May inactivate DNA repair enzymes
crosslinking

13. Alkylating agents Busulfan Notes
Synthetic agent used as an anticancer agent
Causes interstrand crosslinking
Curly arrows
Crosslinking
Wiggly lines and brackets

14. Alkylating agents Dacarbazine
Prodrug activated by demethylation in liver
Decomposes to form a methyldiazonium ion
Alkylates guanine groups

15. Alkylating agents Mitomycin C
Prodrug activated in the body to form an alkylating agent
One of the most toxic anticancer drugs in clinical use

16. -MeOH
Reduction
Ring
opening
-H +
Alkylating agent
-CO2
-NH3
Crosslinked DNA

17. Alkylating agents CC1065 Naturally occurring agent
Binds to minor groove of DNA
Alkylates adenine bases
1000 times more active than cisplatin in vitro

18. Alkylating agents Adozelesin Simplified synthetic analogue of CC 1065
Possible use in antibody-drug conjugates

19. Metallating agents Cisplatin
Neutral inactive molecule acting as a prodrug
Platinum covalently linked to chloro substituents
Ammonia molecules act as ligands
Activated in cells with low chloride ion concentration
Chloro substituents are replaced with neutral water ligands
Produces positively charged species that react with DNA

20. Metallating agents Cisplatin
Binds to DNA in regions rich in guanine units
Intrastrand links are formed rather than interstrand
Causes localised unwinding of the DNA double helix
Inhibits transcription

21. Metallating agents Cisplatin analogues Carboplatin Less side effects
JM216
First orally active analogue
Oxaliplatin
Approved in 1999
Picoplatin