Mechanism of Action
Nitrogen mustards (NMs) form cyclic aminium ions (aziridinium rings) by intramolecular displacement of the chloride by the amine nitrogen. This azidirium group then alkylates DNA by attacking the N-7 nucleophilic center on the guanine base. A second attack after the displacement of the second chlorine forms the second alkylation step that results in the formation of interstrand cross-links (ICLs) as it was shown in the early 1960s. At that time it was proposed that the ICLs were formed between N-7 atom of guanine residue in a 5’-d(GC) sequence. These kind of lesion are highly cytotoxic, since they block fundamental metabolic processes such as replication and transcription.
Later it was clearly demonstrated that NMs form a 1,3 ICL in the 5’-d(GNC) sequence.
The strong cytotoxic effect caused by the formation of ICLs is what makes NMs an effective chemotherapeutic agent. Other compounds used in cancer chemotherapy that have the ability to form ICLs are cisplatin, mitomycin C, carmustine, and psoralen.
Read more about this topic: Nitrogen Mustard
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