Nitrogen mustard

Nitrogen mustard
HN1 (bis(2-chloroethyl)ethylamine)
HN2 (bis(2-chloroethyl)methylamine, mustine)
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 and the main examples (HN1, HN2, HN3, see below) are therefore classified as Schedule 1 substances within the Chemical Weapons Convention. Production and use is therefore strongly restricted.

During WWII nitrogen mustards were studied at Yale University and classified human clinical trials of nitrogen mustards for the treatment of lymphoma started in December 1942.[1] Also during WWII, an incident during the air raid on Bari, Italy led to the release of mustard gas that affected several hundred soldiers and civilians. Medical examination of the survivors showed a decreased number of lymphocytes.[2] After WWII 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.

Examples

The original nitrogen mustard drug, mustine (HN2), is no longer commonly in use. Other nitrogen mustards developed as treatments include cyclophosphamide, chlorambucil, uramustine, ifosfamide, melphalan and bendamustine. Bendamustine has recently reemerged as a viable chemotheraputic treatment.[3]

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

Mechanism of action

Nitrogen mustards (NMs) form cyclic aminium ions (aziridinium rings) by intramolecular displacement of the chloride by the amine nitrogen. This azidirium group then alkylates DNA by attacking 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.[4][5] These kind of lesion are highly cytotoxic, since they block fundamental metabolic processes such as replication and transcription.

Later was it clearly demonstrated that NMs form a 1,3 ICL in the 5’-d(GNC) sequence.[6][7][8]

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, psoralen.

References

  1. ^ Gilman A (May 1963). "The initial clinical trial of nitrogen mustard". Am. J. Surg. 105 (5): 574–8. doi:10.1016/0002-9610(63)90232-0. PMID 13947966. 
  2. ^ Hirsch J (September 2006). "An anniversary for cancer chemotherapy". JAMA 296 (12): 1518–20. doi:10.1001/jama.296.12.1518. PMID 17003400. 
  3. ^ Cheson BD, Rummel MJ (March 2009). "Bendamustine: rebirth of an old drug". J. Clin. Oncol. 27 (9): 1492–501. doi:10.1200/JCO.2008.18.7252. PMID 19224851. http://www.jco.org/cgi/pmidlookup?view=long&pmid=19224851. 
  4. ^ Geiduschek EP (July 1961). ""Reversible" DNA". Proc. Natl. Acad. Sci. U.S.A. 47 (7): 950–5. doi:10.1073/pnas.47.7.950. PMC 221307. PMID 13704192. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=221307. 
  5. ^ Brookes P, Lawley PD (September 1961). "The reaction of mono- and di-functional alkylating agents with nucleic acids". Biochem. J. 80 (3): 496–503. PMC 1243259. PMID 16748923. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1243259. 
  6. ^ 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. 
  7. ^ Dong Q, Barsky D, Colvin ME, et al. (December 1995). "A structural basis for a phosphoramide mustard-induced DNA interstrand cross-link at 5'-d(GAC)". Proc. Natl. Acad. Sci. U.S.A. 92 (26): 12170–4. doi:10.1073/pnas.92.26.12170. PMC 40318. PMID 8618865. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8618865. 
  8. ^ Bauer GB, Povirk LF (March 1997). "Specificity and kinetics of interstrand and intrastrand bifunctional alkylation by nitrogen mustards at a G-G-C sequence". Nucleic Acids Res. 25 (6): 1211–8. doi:10.1093/nar/25.6.1211. PMC 146567. PMID 9092631. http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9092631. 
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Ethyldichloroarsine (ED) · Methyldichloroarsine (MD) · Phenyldichloroarsine (PD) · Lewisite (L) · Sulfur mustard (HD · H · HT · HL · HQ) · Nitrogen mustard (HN1 · HN2 · HN3)
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Look at other dictionaries:

  • nitrogen mustard — n any of various toxic blistering compounds analogous to mustard gas but containing nitrogen instead of sulfur esp mechlorethamine * * * see chlormethine * * * 1. mechlorethamine hydrochloride. 2. any of a group of cytotoxic alkylating agents… …   Medical dictionary

  • nitrogen mustard — n. any of a class of compounds similar to mustard gas, but having an amino nitrogen in place of a sulfur atom: used in the treatment of cancers, etc …   English World dictionary

  • nitrogen mustard — nitrogen mustard. См. азотистый иприт. (Источник: «Англо русский толковый словарь генетических терминов». Арефьев В.А., Лисовенко Л.А., Москва: Изд во ВНИРО, 1995 г.) …   Молекулярная биология и генетика. Толковый словарь.

  • nitrogen mustard — azoto ipritas statusas T sritis chemija formulė RN(CH₂CH₂Cl)₂; čia R=–CH₂CH₂Cl, –C₂H₅ arba –CH₃ atitikmenys: angl. nitrogen mustard rus. азотистый иприт …   Chemijos terminų aiškinamasis žodynas

  • nitrogen-mustard gas — azoto ipritas statusas T sritis apsauga nuo naikinimo priemonių apibrėžtis Pūliuojamoji patvarioji kovinė nuodingoji medžiaga. Šviežios žuvies kvapo geltonai rudas riebalingas skystis. Pagrindinė kovinė būsena – lašai. Lydymosi temperatūra 60 °C …   Apsaugos nuo naikinimo priemonių enciklopedinis žodynas

  • nitrogen mustard — noun Date: 1943 any of various toxic blistering compounds analogous to mustard gas but containing nitrogen instead of sulfur …   New Collegiate Dictionary

  • nitrogen mustard — Chem. any of the class of poisonous, blistering compounds, as C5H11Cl2N, analogous in composition to mustard gas but containing nitrogen instead of sulfur: used in the treatment of cancer and similar diseases; mechlorethamine. [1945 50] * * * …   Universalium

  • nitrogen mustard — noun any of a series of compounds, analagous to mustard gas with sulfur replaced by nitrogen, that have been used in the treatment of cancer …   Wiktionary

  • nitrogen mustard — noun a toxic compound resembling mustard gas in structure; important in cancer treatment • Hypernyms: ↑compound, ↑chemical compound …   Useful english dictionary

  • HN3 (nitrogen mustard) — Tris(2 chloroethyl)amine …   Wikipedia

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