Alkylating Agents Flashcards
What are the types of nitrogen mustards?
mechlorethamine - mustargen
chlorambucil - leukeran
How do nitrogen mustards work?
the nitrogen mustard displaces a chlorine atom to form an aziridinium ion (3 membered, highly strained nitrogen ring)
nucleophilic N7 guanine attacks the mono adduct to form a monoalkylated adduct
monoalkylated adduct reacts with another N7 guanine closing the ring
- cytotoxicity is through the crosslinks which prevent DNA from uncoiling during replication
= blocks DNA replication
How do nitrogen mustards attack cancer cells specifically?
mechanism of action is based on proliferation probability
- attack the rapidly dividing cancerous cells allowing for selectivity
Why is chlorambucil a weaker alkylating agent?
chlorambucil has aniline character (N attached to a benzene ring)
- are weaker bases and nucleophiles
- means it can form resonance structures which prevent it from forming aziridinium ions
What are the types of platins? What is the difference between them?
cisplatin
- has ammonia and chloride ions
carboplatin
- chloride ions are replaced with bidentate oxalate type ligands
= makes it less cytotoxic and reactive than cisplatin
oxaliplatin
Why is carboplatin less cytotoxic than cisplatin? What are they used to treat?
carboplatin has a bidenate oxalate ligand
- has lower excretion rates meaning its retained in the body for longer
- are less reactive due to poor leaving groups
- slower DNA binding
makes them it less toxic and has fewer side effects
treat
- ovarian, lung, head and neck cancer
- neuroblastoma
What is the difference between cisplatin and transplatin?
cisplatin forms intrastrand crosslinks
- DNA is poorly repaired
= due to cis chloride ions
transplatin forms interstrand crosslinks
- DNA is repaired more efficiently
= due to trans chloride ions
transplatin is inactive
What is temozolomide? What is temozolomide (TMZ) used to treat?
is a imidazotetrazine prodrug
treats brain tumours
- glioma
How does temozolomide work?
is a prodrug
- active form is MTIC
TMZ degradation releases methyldiazonium cation which can act in two ways
- acts as a methylation agent at the nucleophilic sites of guanine
= N6 and N7
N6
- adds a methyl group to the guanine residue of DNA at N6/O6
- deoxyribose backbone is not cleaved
N7
- adds a methyl group to the guanine residue of DNA at N7
- N2 acts as a leaving group
- deoxyribose backbone is broken
How does temozolomide resistance occur?
some tumours can repair DNA by expressing the protein O6-methylguanine DNA methyltransferase (MGMT)
MGMT methylates at the N6 position repairing and regenerating the guanine
- O-6-MeG lesions result in chemoresistance
What is dacarbazine? How is it related to MTIC? What is it used to treat? What are the disadvantages of it?
is an imidazole carboxamide
- MTIC (bioactive form of TMZ) is a derivative of it
- only differs with MTIC having 1xCH3 and 1xH vs DTIC having 2xCH3
treats
- melanoma, hodgkin’s lymphoma, sarcoma and islet cell carcinoma in pancreatic cancer
What are the disadvantages of dacarbazine?
has poor oral absorption
- given intravenously
is light sensitive
- breaks down back to diazonium salt which cyclizes to inactive imidazotetrazine
