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Nitrogen mustards are cytotoxic organic compounds with the chloroethylamine (Cl(CH2)2NR2) functional group. Although originally produced as
chemical warfare Chemical warfare (CW) involves using the toxic properties of chemical substances as weapons. This type of warfare is distinct from nuclear warfare, biological warfare and radiological warfare, which together make up CBRN, the military a ...
agents, they were the first chemotherapeutic agents for treatment of cancer. Nitrogen mustards are nonspecific DNA alkylating agents.


Chemical warfare

During World War II nitrogen mustards were studied at the
Yale School of Medicine The Yale School of Medicine is the graduate medical school at Yale University, a private research university in New Haven, Connecticut. It was founded in 1810 as the Medical Institution of Yale College and formally opened in 1813. The primary te ...
by Alfred Gilman and Louis Goodman, and classified human clinical trials of nitrogen mustards for the treatment of
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include en ...
started in December 1942. Also during World War II, an incident during the air raid on Bari, Italy, led to the release of
mustard gas Mustard gas or sulfur mustard is a chemical compound belonging to a family of cytotoxic and blister agents known as mustard agents. The name ''mustard gas'' is technically incorrect: the substance, when dispersed, is often not actually a gas, ...
that affected several hundred soldiers and civilians. Medical examination of the survivors showed a decreased number of lymphocytes. 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 Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
drug
mustine Chlormethine (INN, BAN), also known as mechlorethamine (USAN, USP), mustine, HN2, and (in post-Soviet states) embikhin (эмбихин), is a nitrogen mustard sold under the brand name Mustargen among others. It is the prototype of alkylating ...
. Nitrogen mustards are not related to the mustard plant or its pungent essence,
allyl isothiocyanate Allyl isothiocyanate (AITC) is an organosulfur compound (formula CH2CHCH2NCS). This colorless oil is responsible for the pungent taste of mustard, radish, horseradish, and wasabi. This pungency and the lachrymatory effect of AITC are mediated thr ...
; the name comes from the pungent smell of chemical weapons preparations.


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 Chlorambucil, sold under the brand name Leukeran among others, is a chemotherapy medication used to treat chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, and non-Hodgkin lymphoma. For CLL it is a preferred treatment. It is given by mouth. ...
,
uramustine Uramustine (INN) or uracil mustard is a chemotherapy drug which belongs to the class of alkylating agents. It is used in lymphatic malignancies such as non-Hodgkin's lymphoma. It works by damaging DNA, primarily in cancer cells that preferentia ...
, melphalan, and
bendamustine Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by injection into a vein. Common si ...
.
Bendamustine Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by injection into a vein. Common si ...
has recently re-emerged as a viable chemotherapeutic treatment. Nitrogen mustards that can be used for chemical warfare purposes are tightly regulated. Their weapon designations are: * HN1:
Bis(2-chloroethyl)ethylamine Bis(2-chloroethyl)ethylamine is the organic compound with the formula C2H5N(CH2CH2Cl)2. Often abbreviated HN1, it is a powerful vesicant and a nitrogen mustard gas used for chemical warfare. HN1 was developed in the 1920s and 1930s to remove ...
* HN2: Bis(2-chloroethyl)methylamine * HN3:
Tris(2-chloroethyl)amine Tris(2-chloroethyl)amine is the organic compound with the formula N(CH2CH2Cl)3. Often abbreviated HN3 or HN-3, it is a powerful blister agent and a nitrogen mustard used for chemical warfare. HN3 was the last of the nitrogen mustard agents deve ...
Nor-mustard can be used in the synthesis of piperazine drugs. For example,
mazapertine Mazapertine (RWJ-37796) is an antipsychotic agent that was developed by Johnson & Johnson Johnson & Johnson (J&J) is an American multinational corporation founded in 1886 that develops medical devices, pharmaceuticals, and consumer packaged ...
, aripiprazole &
fluanisone Fluanisone is a typical antipsychotic and sedative of the butyrophenone chemical class. It is used in the treatment of schizophrenia and mania. It is also a component (along with fentanyl) of the injectable veterinary formulation fentanyl/fl ...
. 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 Chlornaltrexamine is an irreversible mixed agonist–antagonist for μ- opioid receptors, which forms a covalent bond to the active site. It is 22 times more potent than morphine. Its alkylating group is a bis(chloroalkyl)amino-residue similar to ...
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. Later it was clearly demonstrated that NMs form a 1,3 ICL in the 5’-d(GNC) sequence. 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 Carmustine, sold under the brand name BiCNU among others, is a medication used mainly for chemotherapy. It is a nitrogen mustard β-chloro- nitrosourea compound used as an alkylating agent. Description Carmustine is an orange-yellow solid medic ...
, and psoralen. 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 agent A blister agent (or vesicant), is a chemical compound that causes severe skin, eye and mucosal pain and irritation. They are named for their ability to cause severe chemical burns, resulting in painful water blisters on the bodies of those affec ...
s. HN1, HN2, HN3 are therefore classified as Schedule 1 substances within the
Chemical Weapons Convention The Chemical Weapons Convention (CWC), officially the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction, is an arms control treaty administered by the Organisation for ...
. Production and use is therefore strongly restricted.


Further reading

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References

{{Detoxifying agents for antineoplastic treatment Blister agents IARC Group 2A carcinogens Cancer treatments