Nitrogen mustard

Short description: Family of chemical compounds

HN1 (bis(2-chloroethyl)ethylamine)

HN2 (bis(2-chloroethyl)methylamine, mustine)

HN3 (tris(2-chloroethyl)amine)

Nitrogen mustards are cytotoxic organic compounds with the chloroethylamine ((ClCH2)2NR2) functional group.[1] Although originally produced as chemical warfare agents,[2][3] they were the first chemotherapeutic agents for treatment of cancer.[4] Nitrogen mustards are nonspecific DNA alkylating agents.

## Contents

* 1 Chemical warfare
* 2 Examples
* 3 Mechanism of action
* 4 Safety
* 5 Further reading
* 6 References

## Chemical warfare

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.[5] 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.[6] Medical examination of the survivors showed a decreased number of lymphocytes.[7] 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.[8]

## Examples

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.[9] Bendamustine has recently re-emerged as a viable chemotherapeutic treatment.[10]

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

Nor-mustard can be used in the synthesis of piperazine drugs. For example, 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 (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.[12][13] Later it was clearly demonstrated that NMs 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, 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]

## Further reading

* Stanford University School of Medicine (2013). "Topical Nitrogen Mustard (Mustargen)". stanford.edu. http://cutaneouslymphoma.stanford.edu/community/mustargen.html.
* University of California, Los Angeles (2002). "Brassica alba or Sinapis nigra". ucla.edu. http://unitproj.library.ucla.edu/biomed/spice/index.cfm?displayID=18.

## References

1. ↑ "Mustards". The IUPAC Compendium of Chemical Terminology. 2014. doi:10.1351/goldbook.M04071. https://goldbook.iupac.org/terms/view/M04071.
2. ↑ Nitrogen mustard gas was stockpiled by several nations during the Second World War, but it was never used in combat.Daniel C. Keyes; Jonathan L. Burstein; Richard B. Schwartz; Raymond E. Swienton (2004). Medical Response to Terrorism: Preparedness and Clinical Practice. Lippincott Williams & Wilkins. pp. 16. ISBN 978-0781749862. https://books.google.com/books?id=y4uCV4Gm82YC&q=Nitrogen+mustard+stockpiled+after+WWII&pg=PA16.
3. ↑ Centers for Disease Control and Prevention (April 4, 2013). "Facts About Nitrogen Mustards". cdc.gov. http://www.bt.cdc.gov/agent/nitrogenmustard/basics/facts.asp.
4. ↑ Chabner, Bruce A.; Roberts, Thomas G. (2005). "Chemotherapy and the war on cancer". Nature Reviews Cancer 5 (1): 65–72. doi:10.1038/nrc1529. PMID 15630416.
5. ↑ 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.
6. ↑ Jules Hirsch, MD; Journal of the American Medical Association (2006). "An Anniversary for Cancer Chemotherapy". JAMA (jamanetwork.com) 296 (12): 1518–1520. doi:10.1001/jama.296.12.1518. PMID 17003400. http://jama.jamanetwork.com/article.aspx?articleid=203402#tab1.
7. ↑ Hirsch J (September 2006). "An anniversary for cancer chemotherapy". JAMA 296 (12): 1518–20. doi:10.1001/jama.296.12.1518. PMID 17003400.
8. ↑ Ghorani-Azam, Adel; Balali-Mood, Mahdi (December 1, 2015). "Clinical Pharmacology and Toxicology of Mustard Compounds". Basic and Clinical Toxicology of Mustard Compounds. Springer. p. 64. ISBN 9783319238746. https://books.google.com/books?id=MGkiCwAAQBAJ&pg=PA64. Retrieved March 12, 2019.
9. ↑ 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. PMID 3960738.
10. ↑ "Bendamustine: rebirth of an old drug". J. Clin. Oncol. 27 (9): 1492–501. March 2009. doi:10.1200/JCO.2008.18.7252. PMID 19224851. http://www.jco.org/cgi/pmidlookup?view=long&pmid=19224851.
11. ↑ University of Durham. "SCHEDULE 1 CHEMICALS". dur.ac.uk. https://www.dur.ac.uk/resources/healthandsafety/office/CWAschedule1.pdf.
12. ↑ Geiduschek EP (July 1961). ""Reversible" DNA". Proc. Natl. Acad. Sci. U.S.A. 47 (7): 950–5. doi:10.1073/pnas.47.7.950. PMID 13704192. Bibcode: 1961PNAS...47..950G.
13. ↑ "The reaction of mono- and di-functional alkylating agents with nucleic acids". Biochem. J. 80 (3): 496–503. September 1961. doi:10.1042/bj0800496. PMID 16748923.
14. ↑ "Mechlorethamine Cross Links Deoxyguanosine Residues at 5'-GNC Sequences in Duplex DNA Fragments". Journal of the American Chemical Society 112 (6): 2459–60. 1990. doi:10.1021/ja00162a079.
15. ↑ "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. 1993. doi:10.1021/ja00060a001.
16. ↑ "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. December 1995. doi:10.1073/pnas.92.26.12170. PMID 8618865. Bibcode: 1995PNAS...9212170D.
17. ↑ "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. March 1997. doi:10.1093/nar/25.6.1211. PMID 9092631.
18. ↑ 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.
19. ↑ Organisation for the Prohibition of Chemical Weapons. "Chemical Weapons Convention: Schedule 1 Toxic chemicals". opcw.org. http://www.opcw.org/chemical-weapons-convention/annex-on-chemicals/b-schedules-of-chemicals/schedule-1/.
20. ↑ 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". cwc.gov. http://www.cwc.gov/assets/pdf/outreach_industry_publications_cwc004.pdf.

* v
* t
* e

* Agents used in chemical warfare
* incapacitation
* riot control

Blood|

* Cyanogen
* Cyanogen bromide
* Cyanogen chloride (CK)
* Hydrogen cyanide (AC)
* Arsine
* Vinyl arsine

Blister|

* Arsenicals
* Ethyldichloroarsine (ED)
* Methyldichloroarsine (MD)
* Phenyldichloroarsine (PD)
* Lewisite (L)
* Mustard gas (HD H HT HL HQ)
* Nitrogen mustard
* HN1
* HN2
* HN3
* TL-301
* Nitrosocarbamates
* KB-16

Nerve|

| G-agents|

* Tabun (GA)
* Sarin (GB)
* Chlorosarin (GC)
* Soman (GD)
* Ethylsarin (GE)
* Cyclosarin (GF)
* GH
* GJ
* GK
* GL
* GM
* GN
* GO
* GP
* GQ
* GR
* GS
* GT
* GU
* Fluorotabun
* GV
* GV1
* GV2
* GV3
* GV4
* GV5
* GV6
* EA-1356
* EA-3534
* EA-4352
* EA-5414
* EA-5488
* Thiosarin
* Thiosoman
* Thiocyclosarin
* Crotylsarin

|

V-agents|

* EA-2192
* EA-3148
* EA-3317
* VD
* VE
* VF
* VG
* VH
* VJ
* VK
* VL
* VM
* VN
* VO
* VP
* VQ
* VR
* VS
* VT
* VU
* VV
* VW
* VY
* VZ
* VX
* V1
* V2
* V3
* V4
* V5
* V6
* IVX
* IIVx
* Chinese VX
* V-sub x (GD-7)

Novichok agents|

* A-230
* A-232
* A-234
* A-242
* A-262
* C01-A035
* C01-A039
* C01-A042

Carbamates|

* EA-3887
* EA-3887A
* EA-3948
* EA-3966
* EA-3990
* EA-4026
* EA-4038
* EA-4048
* EA-4056
* EA-4057
* EA-4181
* T-1123
* Octamethylene-bis(5-dimethylcarbamoxyisoquinolinium bromide)

Other|

* EA-2012
* EA-2054
* EA-2098
* EA-2613
* 2-Ethoxycarbonyl-1-methylvinyl cyclohexyl methylphosphonate
* Neopentylene fluorophosphate

Precursors|

* Chlorosarin
* Chlorosoman
* Cyclohexanol
* 1,8-Dibromooctane
* N,N-Diisopropylaminoethanol
* Dimethylamidophosphoric dichloride
* Dimethylamidophosphoric dicyanide
* Isopropyl alcohol
* Methyldichlorophosphine
* Methylphosphonic acid dichloride
* Methylphosphonyl difluoride
* Pinacolone
* Pinacolyl alcohol
* QL
* 3,3,5-Trimethylcyclohexanol

Neurotoxins|

* Saxitoxin (TZ)
* Botulinum toxin (BTX)
* Tetanospasmin (TeNT)
* Chlorophenylsilatrane
* Tetrodotoxin

Nettle|

* Phosgene oxime (CX)

Pulmonary/Choking agent|

* Chlorine
* Phosgene (CG)
* Perfluoroisobutene
* Chloropicrin (PS)
* Diphosgene (DP)
* Disulfur decafluoride
* Acrolein
* Ethyl bromoacetate
* Perchloromethyl mercaptan

Vomiting agent|

* Adamsite
* Chloropicrin
* Diphenylchlorarsine
* Diphenylcyanoarsine
* Diphenylaminecyanoarsine

Incapacitating|

* Agent 15 (BZ)
* Dimethylheptylpyran (DMHP)
* EA-3167
* EA-3443
* EA-3580
* EA-3834
* Kolokol-1
* LSD-25
* PAVA spray
* Sleeping gas

Riot control|

* Xylyl bromide
* Pepper spray (OC)
* Mace (spray)
* CN
* CS
* CR
* CNS

Other|

* Methyl fluoroacetate
* Fluoroethyl fluoroacetate
* Ricin
* Abrin
* Enterotoxin type B
* Depleted uranium
* post-combustion uranium oxides

* List of chemical warfare agents
* CB military symbol

* v
* t
* e

Intracellular chemotherapeutic agents / antineoplastic agents (L01)

SPs/MIs
(M phase)|

| Block microtubule assembly|

* Vinca alkaloids (Vinblastine#
* Vincristine#
* Vinflunine§
* Vindesine
* Vinorelbine#)

|

Block microtubule disassembly|

* Taxanes (Cabazitaxel
* Docetaxel#
* Larotaxel
* Ortataxel†
* Paclitaxel#
* Tesetaxel)
* Epothilones (Ixabepilone)

DNA replication
inhibitor|

| DNA precursors/
antimetabolites
(S phase)|

| Folic acid|

* Dihydrofolate reductase inhibitor (Aminopterin
* Methotrexate#
* Pemetrexed
* Pralatrexate)
* Thymidylate synthase inhibitor (Raltitrexed
* Pemetrexed)

|

Purine|

* Adenosine deaminase inhibitor (Pentostatin)

* Halogenated/ribonucleotide reductase inhibitors (Cladribine
* Clofarabine
* Fludarabine)
* Nelarabine

* Thiopurine (Tioguanine#
* Mercaptopurine#)

Pyrimidine|

* Thymidylate synthase inhibitor (Fluorouracil#
* Capecitabine#
* Doxifluridine
* Tegafur (+gimeracil/oteracil)
* Carmofur
* Floxuridine)

* DNA polymerase inhibitor (Cytarabine#)

* Ribonucleotide reductase inhibitor (Gemcitabine#)

* Hypomethylating agent (Azacitidine
* Decitabine)

Deoxyribonucleotide|

* Ribonucleotide reductase inhibitor (Hydroxycarbamide#)

Topoisomerase inhibitors
(S phase)|

| I|

* Camptotheca (Camptothecin
* Cositecan†
* Belotecan
* Gimatecan
* Exatecan
* Irinotecan#
* Lurtotecan‡
* Silatecan§
* Topotecan
* Rubitecan‡)

|

II|

* Podophyllum (Etoposide#
* Teniposide)

II+Intercalation|

* Anthracyclines (Aclarubicin
* Daunorubicin#
* Doxorubicin#
* Epirubicin
* Idarubicin
* Amrubicin†
* Pirarubicin
* Valrubicin
* Zorubicin)
* Anthracenediones (Mitoxantrone
* Pixantrone)

Crosslinking of DNA
(CCNS)|

| Alkylating|

* Nitrogen mustards: Chlormethine
* Cyclophosphamide# (Ifosfamide#
* Trofosfamide)
* Chlorambucil# (Melphalan
* Prednimustine)
* Bendamustine#
* Uramustine

* Nitrosoureas: Carmustine
* Lomustine (Semustine)
* Fotemustine
* Nimustine
* Ranimustine
* Streptozocin

* Alkyl sulfonates: Busulfan (Mannosulfan
* Treosulfan)

* Aziridines: Carboquone
* Thiotepa
* Triaziquone
* Triethylenemelamine

|

Platinum-based|

* Carboplatin#
* Cisplatin#
* Dicycloplatin
* Nedaplatin
* Oxaliplatin#
* Satraplatin

Nonclassical|

* Hydrazines (Procarbazine#)
* Triazenes (Dacarbazine#
* Temozolomide)
* Altretamine
* Mitobronitol
* Pipobroman

Intercalation|

* Streptomyces (Actinomycin#
* Bleomycin#
* Mitomycins
* Plicamycin)

Photosensitizers/PDT|

* Aminolevulinic acid / Methyl aminolevulinate
* Efaproxiral
* Porphyrin derivatives (Porfimer sodium
* Talaporfin
* Temoporfin
* Verteporfin)

Other|

| Enzyme inhibitors|

* FI (Tipifarnib§)
* CDK inhibitors (Abemaciclib
* Alvocidib†
* Palbociclib
* Ribociclib
* Seliciclib†)
* PrI
* Bortezomib
* Carfilzomib
* Ixazomib
* PhI (Anagrelide)
* IMPDI (Tiazofurin§)
* LI (Masoprocol)
* PARP inhibitor (Niraparib
* Olaparib
* Rucaparib)
* HDAC (Belinostat
* Panobinostat
* Romidepsin
* Vorinostat)
* PIKI (Idelalisib)

|

Receptor antagonists|

* ERA (Atrasentan)
* Retinoid X receptor (Bexarotene)
* Sex steroid (Testolactone)

Other/ungrouped|

* Amsacrine
* Trabectedin
* Retinoids (Alitretinoin
* Tretinoin#)
* Arsenic trioxide
* Asparagine depleters (Asparaginase#/Pegaspargase)
* Celecoxib
* Demecolcine
* Elesclomol§
* Elsamitrucin
* Estramustine phosphate
* Etoglucid
* Lonidamine
* Lucanthone
* Mitoguazone
* Mitotane
* Oblimersen†
* Omacetaxine mepesuccinate
* Eribulin

* #WHO-EM
* ‡Withdrawn from market
* Clinical trials:
* †Phase III
* §Never to phase III

* v
* t
* e

Detoxifying agents for chemotherapy treatment (V03AF)

Folic acid / methotrexate|

* Salts of Folinic acid
* calcium folinate/calcium levofolinate
* sodium folinate/sodium levofolinate

Uric acid (TLS)|

* Rasburicase

Acrolein / nitrogen mustards|

* Mesna

Iron / anthracyclines|

* Dexrazoxane

Alkylating agents|

* Amifostine

Keratinocyte growth factor|

* Palifermin

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