Nitrogen mustard

Source: Wikipedia, the free encyclopedia.
bis(2-chloroethyl)ethylamine
)
bis(2-chloroethyl)methylamine
, mustine)
tris(2-chloroethyl)amine
)

Nitrogen mustards (NMs) are

alkylating agents
.

Name

Nitrogen mustards are not related to the mustard plant or its pungent essence, allyl isothiocyanate; the name comes from the pungent smell of chemical weapons preparations.[5]

Chemical warfare

During World War II, nitrogen mustards were studied at the

mustine
.

Examples

The nitrogen mustard drug

mustine (HN2), is no longer commonly in use in its original IV formulation because of excessive toxicity. Other nitrogen mustards developed include cyclophosphamide, chlorambucil, uramustine, melphalan, and bendamustine.[9] Bendamustine has recently re-emerged as a viable chemotherapeutic treatment.[10]

Nitrogen mustards that can be used for chemical warfare purposes are tightly regulated. Their weapon designations are:[11]

  • HN1:
    bis(2-chloroethyl)ethylamine
  • HN2:
    bis(2-chloroethyl)methylamine
  • HN3:
    tris(2-chloroethyl)amine

Normustard (mustine without a methyl group on the nitrogen atom; bis(2-chloroethyl)ethylamine) can be used in the synthesis of piperazine drugs such as mazapertine, aripiprazole & fluanisone. Canfosfamide was also made from normustard.

Some nitrogen mustards of opiates were also prepared, although these are not known to be antineoplastic. Examples include chlornaltrexamine and chloroxymorphamine.

Mechanism of action

Nitrogen mustards form cyclic ammonium ions (aziridinium ions) by intramolecular displacement of the chloride by the amine nitrogen. This aziridinium group then alkylates DNA once it is attacked by 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.[12][13] Later it was clearly demonstrated that nitrogen mustards form a 1,3 ICL in the 5’-d(GNC) sequence.[14][15][16][17]

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.[18] These kinds of lesions are effective at forcing the cell to undergo apoptosis via p53,[citation needed] a protein which scans the genome for defects. Note that the alkylating damage itself is not cytotoxic and does not directly cause cell death.

Safety

Nitrogen mustards are powerful and persistent blister agents. HN1, HN2, HN3 are therefore classified as Schedule 1 substances within the Chemical Weapons Convention.[19] Production and use is therefore strongly restricted.[20]

See also

References

Further reading