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HN1 (bis(2-chloroethyl)ethylamine)

HN2 (bis(2-chloroethyl)methylamine)

HN3 (tris(2-chloroethyl)amine)

The nitrogen mustards are cytotoxic chemotherapy agents similar to mustard gas. Although their common use is medicinal, in principle these compounds can also be deployed as chemical warfare agents. Nitrogen mustards are nonspecific DNA alkylating agents. Nitrogen mustard gas was stockpiled by several nations during the Second World War, but it was never used in combat. As with all types of mustard gas, nitrogen mustards are powerful and persistent blister agents. The drug mustin was developed after a war accident in 1943 in Bari, Italy where civilians and soldiers were exposed to mustard gas. It was observed that survivors had a decreased number of lymphocytes suggesting a possible therapy to cure lymphomas.

Examples

The prototype nitrogen mustard drug is mustine, which is no longer commonly in use. It was the first anticancer chemotherapeutic drug. It is a schedule 1 substance in the Chemical Weapons Convention. Other nitrogen mustards include cyclophosphamide, chlorambucil, uramustine, ifosfamide, melphalan and bendamustine that had recently reemerged ^[1]

Examples of nitrogen mustards that can be used for chemical warfare purposes and their weapon designations include:

• HN1: Bis(2-chloroethyl) ethylamine
• HN2: Bis(2-chloroethyl) methylamine
• HN3: Tris(2-chloroethyl) amine

Mechanism of action

Nitrogen mustards form cyclic aminium ions (aziridinium rings) by intramolecular displacement of the chloride by the amine nitrogen. This azidirium group then alkylates basic centers on the DNA. Alkylated DNA malfunctions in replication. The therapeutically useful alkylating agents have more than one alkylating group per molecule, i.e. they are di- or polyalkylating agent. The effects are "radiomimetic," i.e. the DNA damage is similar to that which is seen when genetic material is exposed to radiation.

In the early 1960s, NMs were reported to form interstrand crosslinks (ICLs). At that time it was proposed that the ICLs were formed between N-7 atom of guanine residue in a 5’-d(GC) sequence.^[2][3] Later was it clearly demonstrated that NM form a 1,3 ICL in the 5’-d(GNC) sequence.^[4][5][6]

References