1. Patrick: An Introduction to Medicinal Chemistry 6e
Chapter 21
ANTICANCER AGENTS
ALKYLATING AND
METALLATING AGENTS
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

3. Alkylating agents Crosslinking Intrastrand crosslinking
Interstrand crosslinking

4. Alkylating agents Nucleophilic groups on nucleic acid bases
Cytosine
Guanine
Adenine
Nucleophilic
groups
Replaced captions indicating nucleophilic groups and arrows

5. Alkylating agents
Miscoding resulting from alkylated nucleic acid bases
N-Alkylated guanine
Thymine
Cytosine
Guanine
Guanine prefers keto tautomer
Normal base pairing to cytosine
Alkylated guanine prefers enol tautomer
Abnormal base pairing to thymine
Modified

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

7. Alkylating agents Chlormethine Mechanism of action Crosslinked DNA
Mechlorethamine
Aziridine ion
Modified
mechlorethamine redrawn
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
All structures redrawn
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

10. Alkylating agents Cyclophosphamide Notes
Cytochrome P450 enzymes
Cyclophosphamide
R = CH2CH2Cl
Alkylating agent
Acrolein
Modified
Third and fourth structures redrawn
Notes
Cyclophosphamide is the most commonly used alkylating agent
Non-toxic prodrug
Orally active
Acrolein is associated with toxicity

11. (carbamoylating agent)
Alkylating agents
Nitrosoureas
Lomustine
Carmustine
Notes
Decompose in the body to form an alkylating agent and a carbamoylating agent
Top structures redrawn
Isocyanate
(carbamoylating agent) +
Alkylating agent

12. Alkylating agents Nitrosoureas Notes
DNA
Akylation
Cross linking
Isocyanate
Protein-Lys-NH2
Carbamoylation
Protein-Lys-NH
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
Diagrams redrawn

13. Alkylating agents Busulfan Notes
Synthetic agent used as an anticancer agent
Causes interstrand crosslinking
-MeSO3-
Modified
Busulfan redrawn
-MeSO3-

14. Alkylating agents Dacarbazine
Prodrug activated by demethylation in liver
Decomposes to form a methyldiazonium ion
Alkylates guanine groups
Cyt P-450
Liver
-CH2O
N CH3

15. Alkylating agents Mitomycin C
Modified
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
Modified
all structures redrawn aprt from last one
-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
DNA +
H2O
Cisplatin 2+
Modified
Lower Diagram redrawn

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 Satraplatin (JM216)
Less side effects
Satraplatin (JM216)
First orally active analogue
Oxaliplatin
Approved in 1999
Modified
Satraplatin redrawn