Nitrogen mustard
Nitrogen mustards (NMs) are
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
Examples
The nitrogen mustard drug
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
- Mustard gas
- Sulphur mustard
References
- .
- ISBN 978-0781749862– via books.google.com.
- ^ Centers for Disease Control and Prevention (April 4, 2013). "Facts About Nitrogen Mustards". cdc.gov. Archived from the original on September 3, 2013. Retrieved September 12, 2013.
- S2CID 205467419.
- ISBN 9783319238746. Retrieved March 12, 2019 – via Google Books.
- PMID 13947966.
- PMID 17003400.
- PMID 17003400.
- PMID 3960738.
- PMID 19224851.[permanent dead link]
- University of Durham. "SCHEDULE 1 CHEMICALS"(PDF). dur.ac.uk.
- PMID 13704192.
- PMID 16748923.
- .
- .
- PMID 8618865.
- PMID 9092631.
- PMID 20730555.
- ^ Organisation for the Prohibition of Chemical Weapons. "Chemical Weapons Convention: Schedule 1 Toxic chemicals". opcw.org. Archived from the original on 2013-06-07.
- ^ United States Department of State, Bureau of Arms Control, Verification and Compliance; United States Department of Commerce, Bureau of Industry and Security (May 2004). "Introduction to Industry Implementation of the Chemical Weapons Convention" (PDF). cwc.gov. Archived from the original (PDF) on 2013-10-20. Retrieved 2013-09-12.
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Further reading
- Stanford University School of Medicine (2013). "Topical Nitrogen Mustard (Mustargen)". stanford.edu.
- University of California, Los Angeles (2002). "Brassica alba or Sinapis nigra". ucla.edu.