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,[1][2] in principle these compounds can also be deployed as chemical warfare agents.[3][4] 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.[5][6] 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.[7] Production and use is therefore strongly restricted.[8]

During World War II nitrogen mustards were studied at the Yale School of Medicine by Alfred Gilman and Louis Goodman, and classified human clinical trials of nitrogen mustards for the treatment of lymphoma started in December 1942.[9] Also during World War II, an incident during the air raid on Bari, Italy, led to the release of mustard gas that affected several hundred soldiers and civilians.[10] Medical examination of the survivors showed a decreased number of lymphocytes.[11] 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.

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.

Examples

The original nitrogen mustard drug, mustine (HN2), is no longer commonly in use because of excessive toxicity. Other nitrogen mustards developed as treatments include cyclophosphamide, chlorambucil, uramustine, ifosfamide, melphalan, and bendamustine.[12] Bendamustine has recently re-emerged as a viable chemotherapeutic treatment.[13]

Nitrogen mustards that can be used for chemical warfare purposes are tightly regulated. Their weapon designations are:[14]

Nor-mustard can be used in the synthesis of piperazine drugs. For example, mazapertine, aripiprazole & fluanisone. Canfosfamide was also made from normustard.

Mechanism of action

Nitrogen mustards (NMs) form cyclic aminium ions (aziridinium rings) 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.[15][16] These kinds of lesions are effective at forcing the cell to undergo apoptosis via p53, a protein which scans the genome for defects. Note that the alkylating damage itself is not cytotoxic and does not directly cause cell death.

Later it was clearly demonstrated that NMs form a 1,3 ICL in the 5’-d(GNC) sequence.[17][18][19]

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.[20]

References

  1. ↑ Stanford University School of Medicine (2013). "Topical Nitrogen Mustard (Mustargen)". stanford.edu.
  2. ↑ University of California, Los Angeles (2002). "Brassica alba or Sinapis nigra". ucla.edu.
  3. ↑ Mahdi Balali-Mood, Mehrdad Hefazi, MD; Iranian Journal of Medical Sciences (2005). "THE CLINICAL TOXICOLOGY OF SULFUR MUSTARD" (PDF). Iranian Academy of Medical Sciences. pp. 162–179.
  4. ↑ Centers for Disease Control and Prevention. "SULFUR MUSTARD: HEALTH EFFECTS" (PDF). cdc.gov.
  5. ↑ Daniel C. Keyes; Jonathan L. Burstein; Richard B. Schwartz; Raymond E. Swienton (2004). Medical Response to Terrorism: Preparedness and Clinical Practice. Lippincott Williams & Wilkins. p. 16. ISBN 978-0781749862 – via books.google.com.
  6. ↑ Centers for Disease Control and Prevention (April 4, 2013). "Facts About Nitrogen Mustards". cdc.gov.
  7. ↑ Organisation for the Prohibition of Chemical Weapons. "Chemical Weapons Convention: Schedule 1 Toxic chemicals". opcw.org.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ Jules Hirsch, MD; Journal of the American Medical Association (2006). "An Anniversary for Cancer Chemotherapy". jamanetwork.com. pp. 1,518.
  11. ↑ Hirsch J (September 2006). "An anniversary for cancer chemotherapy". JAMA. 296 (12): 1518–20. doi:10.1001/jama.296.12.1518. PMID 17003400.
  12. ↑ Mattes, W. B.; Hartley, J. A.; Kohn, K. W. (1986). "DNA sequence selectivity of guanine–N7 alkylation by nitrogen mustards". Nucleic Acids Research. 14 (7): 2971–2987. doi:10.1093/nar/14.7.2971. PMC 339715Freely accessible. PMID 3960738.
  13. ↑ 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.
  14. ↑ University of Durham. "SCHEDULE 1 CHEMICALS" (PDF). dur.ac.uk.
  15. ↑ Geiduschek EP (July 1961). ""Reversible" DNA". Proc. Natl. Acad. Sci. U.S.A. 47 (7): 950–5. Bibcode:1961PNAS...47..950G. doi:10.1073/pnas.47.7.950. PMC 221307Freely accessible. PMID 13704192.
  16. ↑ 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 1243259Freely accessible. PMID 16748923.
  17. ↑ 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.
  18. ↑ 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. Bibcode:1995PNAS...9212170D. doi:10.1073/pnas.92.26.12170. PMC 40318Freely accessible. PMID 8618865.
  19. ↑ 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 146567Freely accessible. PMID 9092631.
  20. ↑ Guainazzi, A.; Schärer, O. D. (2010). "Using synthetic DNA interstrand crosslinks to elucidate repair pathways and identify new therapeutic targets for cancer chemotherapy". Cellular and Molecular Life Sciences. 67 (21): 3683–3697. doi:10.1007/s00018-010-0492-6. PMID 20730555.
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