Nitrogen mustards (NMs) arecytotoxic organic compounds with the bis(2-chloroethyl)amino ((ClC2H4)2NR) functional group.[1] Although originally produced aschemical warfare agents,[2][3] they were the first chemotherapeutic agents for treatment of cancer.[4] Nitrogen mustards are nonspecific DNAalkylating agents.
Nitrogen mustards are not related to themustard plant or its pungent essence,allyl isothiocyanate; the name comes from the pungent smell of chemical weapons preparations.[5]
During World War II, nitrogen mustards were studied at theYale School of Medicine byAlfred Gilman andLouis Goodman, and in December 1942, they started classified human clinical trials of nitrogen mustards for the treatment oflymphoma.[6] In early December of 1943, an incident during theair raid on Bari, Italy, led to the release ofmustard gas that affected several hundred soldiers and civilians.[7] Medical examination of the survivors showed a decreased number of lymphocytes.[8] After World War II was over, the Bari incident and the Yale group's studies eventually converged prompting a search for other similar compounds. Due to its use in previous studies, the nitrogen mustard known as "HN2" became the firstchemotherapy drugmustine.[citation needed]
Nitrogen mustards form cyclic ammonium ions (aziridinium ions) by intramolecular displacement of the chloride leaving group by the amine nitrogen atom. 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 atom 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 arecisplatin,mitomycin C,carmustine, andpsoralen.[18] These kinds of lesions are effective at forcing the cell to undergo apoptosis viap53,[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.[citation needed]
^Millard JT, Raucher S, Hopkins PB (1990). "Mechlorethamine Cross Links Deoxyguanosine Residues at 5'-GNC Sequences in Duplex DNA Fragments".Journal of the American Chemical Society.112 (6):2459–60.doi:10.1021/ja00162a079.
^Rink SM, Solomon MS, Taylor MJ, Rajur SB, McLaughlin LW, Hopkins PB (1993). "Covalent structure of a nitrogen mustard-induced DNA interstrand cross-link: An N7-to-N7 linkage of deoxyguanosine residues at the duplex sequence 5'-d(GNC)".Journal of the American Chemical Society.115 (7):2551–7.doi:10.1021/ja00060a001.
