nitrogen mustard

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.{{Cite book |chapter-url=https://books.google.com/books?id=MGkiCwAAQBAJ&pg=PA64 |title=Basic and Clinical Toxicology of Mustard Compounds |chapter=Clinical Pharmacology and Toxicology of Mustard Compounds |first1=Adel |last1=Ghorani-Azam |first2=Mahdi |last2=Balali-Mood |publisher=Springer Science+Business Media |isbn=9783319238746 |page=64 |date=December 1, 2015 |access-date=March 12, 2019 |via=Google Books}}

During World War II, nitrogen mustards were studied at the Yale School of Medicine by Alfred Gilman and Louis Goodman, and in December 1942, they started classified human clinical trials of nitrogen mustards for the treatment of lymphoma.{{cite journal |vauthors=Gilman A |title=The initial clinical trial of nitrogen mustard |journal=Am. J. Surg. |volume=105 |pages=574–8 |date=May 1963 |pmid=13947966 |doi=10.1016/0002-9610(63)90232-0 |issue=5 }} In early December of 1943, an incident during the air raid on Bari, Italy, led to the release of mustard gas that affected several hundred soldiers and civilians.{{cite journal | url=http://jama.jamanetwork.com/article.aspx?articleid=203402#tab1 | title=An Anniversary for Cancer Chemotherapy | author=Jules Hirsch, MD | author2=Journal of the American Medical Association | journal=JAMA | volume=296 | issue=12 |pages=1518–1520 | publisher=jamanetwork.com | year=2006| doi=10.1001/jama.296.12.1518 | pmid=17003400 | author2-link=Journal of the American Medical Association }} Medical examination of the survivors showed a decreased number of lymphocytes.{{cite journal |author=Hirsch J |title=An anniversary for cancer chemotherapy |journal=JAMA |volume=296 |issue=12 |pages=1518–20 |date=September 2006 |pmid=17003400 |doi=10.1001/jama.296.12.1518}} 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 first chemotherapy drug mustine.{{cn|date=January 2025}}

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.{{Cite journal | last1=Mattes | first1=W. B. | last2=Hartley | first2=J. A. | last3=Kohn | first3=K. W. | doi=10.1093/nar/14.7.2971 | title=DNA sequence selectivity of guanine–N7 alkylation by nitrogen mustards | journal=Nucleic Acids Research | volume=14 | issue=7 | pages=2971–2987 | year=1986 | pmid=3960738| pmc=339715 }} Bendamustine has recently re-emerged as a viable chemotherapeutic treatment.{{cite journal |vauthors=Cheson BD, Rummel MJ |title=Bendamustine: rebirth of an old drug |journal=J. Clin. Oncol. |volume=27 |issue=9 |pages=1492–501 |date=March 2009 |pmid=19224851 |doi=10.1200/JCO.2008.18.7252 |url=http://www.jco.org/cgi/pmidlookup?view=long&pmid=19224851 |archive-url=https://archive.today/20120803163139/http://www.jco.org/cgi/pmidlookup?view=long&pmid=19224851 |url-status=dead |archive-date=August 3, 2012 }}

Nitrogen mustards that can be used for chemical warfare purposes are tightly regulated. Their weapon designations are:{{cite web | url=https://www.dur.ac.uk/resources/healthandsafety/office/CWAschedule1.pdf | title=SCHEDULE 1 CHEMICALS | author=University of Durham | publisher=dur.ac.uk| author-link=University of Durham }}

• 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.{{cn|date=January 2025}}

Some nitrogen mustards of opiates were also prepared, although these are not known to be antineoplastic. Examples include chlornaltrexamine and chloroxymorphamine.{{cn|date=January 2025}}

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.{{cite journal |author=Geiduschek EP |title="Reversible" DNA |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=47 |pages=950–5 |date=July 1961 |pmid=13704192 |pmc=221307 |doi=10.1073/pnas.47.7.950 |issue=7 |bibcode=1961PNAS...47..950G |doi-access=free }}{{cite journal |vauthors=Brookes P, Lawley PD |title=The reaction of mono- and di-functional alkylating agents with nucleic acids |journal=Biochem. J. |volume=80 |issue=3 |pages=496–503 |date=September 1961 |pmid=16748923 |pmc=1243259 |doi=10.1042/bj0800496 }} Later it was clearly demonstrated that nitrogen mustards form a 1,3 ICL in the 5'-d(GNC) sequence.{{cite journal |vauthors=Millard JT, Raucher S, Hopkins PB |title=Mechlorethamine Cross Links Deoxyguanosine Residues at 5'-GNC Sequences in Duplex DNA Fragments |journal=Journal of the American Chemical Society |volume=112 |pages=2459–60 |year=1990 |doi=10.1021/ja00162a079 |issue=6 }}{{cite journal|vauthors=Rink SM, Solomon MS, Taylor MJ, Rajur SB, McLaughlin LW, Hopkins PB |title=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=Journal of the American Chemical Society |volume=115 |pages=2551–7 |year=1993 |doi=10.1021/ja00060a001 |issue=7 }}{{cite journal |vauthors=Dong Q, Barsky D, Colvin ME, etal |title=A structural basis for a phosphoramide mustard-induced DNA interstrand cross-link at 5'-d(GAC) |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue=26 |pages=12170–4 |date=December 1995 |pmid=8618865 |pmc=40318 |doi=10.1073/pnas.92.26.12170|bibcode=1995PNAS...9212170D |doi-access=free }}{{cite journal |vauthors=Bauer GB, Povirk LF |title=Specificity and kinetics of interstrand and intrastrand bifunctional alkylation by nitrogen mustards at a G-G-C sequence |journal=Nucleic Acids Res. |volume=25 |issue=6 |pages=1211–8 |date=March 1997 |pmid=9092631 |pmc=146567 |url=|doi=10.1093/nar/25.6.1211}}

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.{{Cite journal | last1=Guainazzi | first1=A. | last2=Schärer | first2=O. D. | doi=10.1007/s00018-010-0492-6 | title=Using synthetic DNA interstrand crosslinks to elucidate repair pathways and identify new therapeutic targets for cancer chemotherapy | journal=Cellular and Molecular Life Sciences | volume=67 | issue=21 | pages=3683–3697 | year=2010 | pmid=20730555| pmc=3732395}} These kinds of lesions are effective at forcing the cell to undergo apoptosis via p53,{{Citation needed|date=November 2021}} a protein which scans the genome for defects. Note that the alkylating damage itself is not cytotoxic and does not directly cause cell death.{{cn|date=January 2025}}

Nitrogen mustards are powerful and persistent blister agents. HN1, HN2, HN3 are therefore classified as Schedule 1 substances within the Chemical Weapons Convention.{{cite web | url=http://www.opcw.org/chemical-weapons-convention/annex-on-chemicals/b-schedules-of-chemicals/schedule-1/ | title=Chemical Weapons Convention: Schedule 1 Toxic chemicals | author=Organisation for the Prohibition of Chemical Weapons | publisher=opcw.org | url-status=dead | archive-url=https://web.archive.org/web/20130607201658/http://www.opcw.org/chemical-weapons-convention/annex-on-chemicals/b-schedules-of-chemicals/schedule-1/ | archive-date=2013-06-07 | author-link=Organisation for the Prohibition of Chemical Weapons }} Production and use is therefore strongly restricted.{{cite web | url=http://www.cwc.gov/assets/pdf/outreach_industry_publications_cwc004.pdf | title=Introduction to Industry Implementation of the Chemical Weapons Convention | author=United States Department of State, Bureau of Arms Control, Verification and Compliance; United States Department of Commerce, Bureau of Industry and Security | publisher=cwc.gov | date=May 2004 | access-date=2013-09-12 | archive-url=https://web.archive.org/web/20131020180148/http://www.cwc.gov/assets/pdf/outreach_industry_publications_cwc004.pdf | archive-date=2013-10-20 | url-status=dead }}

{{wikt}}

• Mustard gas
• Sulphur mustard

{{reflist|30em}}

• {{cite web | url=http://cutaneouslymphoma.stanford.edu/community/mustargen.html | title=Topical Nitrogen Mustard (Mustargen) | author=Stanford University School of Medicine | publisher=stanford.edu | year=2013| author-link=Stanford University School of Medicine }}
• {{cite web | url=http://unitproj.library.ucla.edu/biomed/spice/index.cfm?displayID=18 | title=Brassica alba or Sinapis nigra | author=University of California, Los Angeles | publisher=ucla.edu | year=2002| author-link=University of California, Los Angeles }}

{{Nitrogen mustards}}

{{Chemical warfare}}

{{Intracellular chemotherapeutic agents}}

{{Detoxifying agents for antineoplastic treatment}}

Category:Blister agents

Category:IARC Group 2A carcinogens

Category:Cancer treatments