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 | |
| Names | |
|---|---|
| IUPAC name 2-Chloro-N-(2-chloroethyl)-N-methylethanamine | |
| Other names | |
| Identifiers | |
| |
3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
|
| DrugBank |
|
| ECHA InfoCard | 100.000.110 |
| EC Number |
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| KEGG |
|
| MeSH | Mechlorethamine |
| RTECS number |
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| UNII | |
| UN number | 2810 |
| |
| |
| Properties | |
| C5H11Cl2N | |
| Molar mass | 156.05 g·mol−1 |
| Appearance | Colorless liquid |
| Odor | Fishy, ammoniacal |
| logP | 0.91 |
| Pharmacology | |
| D08AX04 (WHO) L01AA05 (WHO) | |
| |
| Pharmacokinetics: | |
| <1 minute | |
| 50% (Kidney) | |
| Legal status | |
| Related compounds | |
Related amines | |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Chlormethine (INN,BAN), also known asmechlorethamine (USAN,USP),mustine,HN2, and (inpost-Soviet states)embikhin (эмбихин), is anitrogen mustard sold under the brand nameMustargen among others. It is the prototype ofalkylating agents, a group ofanticancer chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA baseguanine. As the chemical is ablister agent, its use is strongly restricted within theChemical Weapons Convention where it is classified as aSchedule 1 substance.
Mechlorethamine belongs to the group ofnitrogen mustardalkylating agents.[4][5][6]
It has been derivatized into theestrogen analogueestramustine phosphate, used to treatprostate cancer. It can also be used inchemical warfare where it has the code-nameHN2. This chemical is a form of nitrogenmustard gas and a powerfulvesicant. Historically, some uses of mechlorethamine have included lymphoid malignancies such as Hodgkin's disease, lymphosarcoma, chronic myelocytic leukemia, polycythemia vera, and bronchogenic carcinoma[7] Mechlorethamine is often administered intravenously,[8] but when compounded into a topical formulation it can also be used to treat skin diseases. There have been studies demonstrating that topical administration of mechlorethamine has efficacy in mycosis fungoides-type cutaneous T cell lymphoma.[9][10][11]
Another use of chlormethine is in the synthesis ofpethidine (meperidine).[12]
Mechlorethamine is a highly toxic medication, especially for women who are pregnant, breastfeeding, or of childbearing age.[13][14] At high enough levels, exposure can be fatal.[6]
The adverse effects of mechlorethamine depend on the formulation.[15] When used in chemical warfare, it can cause immunosuppression and damage to mucous membranes of the eyes, skin, and respiratory tract. Mucous membranes and damp or damaged skin are more affected by exposure to HN-2. Though symptoms of exposure are generally delayed, the DNA damage it causes occurs very quickly. More serious exposures cause symptoms to develop sooner. Eye symptoms develop first, in the first 1–2 hours (severe exposure) or 3–12 hours (mild to moderate exposure) followed by airway (2-6/12–24 hours) and skin symptoms (6–48 hours). Hot, humid weather shortens the latent (symptom-free) period.[6]
Symptoms of toxic exposure to HN-2 vary based on the route of exposure. Eye exposure causeslacrimation (tear production), burning, irritation, itching, a feeling of grittiness or dryness,blepharospasm (spasms of the eyelid), andmiosis (pinpoint pupils). More severe cases causeedema (swelling from fluid accumulation) in the eyelids,photophobia (extreme sensitivity to light), severe pain,corneal ulceration, and blindness.[6]
Inhalation of chlormethine damages the upper and lower airways sequentially, with more severe exposures causing faster damage that afflicts lower parts of the respiratory tract. Early symptoms includerhinorrhea (runny nose),epistaxis (nosebleed), toneless voice, sneezing, barking cough, anddyspnea (in smokers and asthmatics). Later symptoms include pain in the nose/sinuses and inflammation of the airway. In severe cases, there may be epithelial necrosis throughout the respiratory tract, causing pseudomembrane formation, which can obstruct the airway.Pneumonia may develop and prove fatal.[6]
Skin exposure mainly causeserythema (redness) andvesication (blistering) at first, but absorption through the skin causes systemic toxicity. In cases where more than 25% of the skin is affected, fatal exposure is likely to have occurred.[6]
Though ingestion is uncommon, if mechlorethamine is swallowed it causes severe chemical burns to the gastrointestinal tract and concomitant nausea, vomiting, diarrhea, abdominal pain, and hemorrhage.[6]
Long-term effects of acute or chronic chlormethine exposure are caused by damage to theimmune system.White blood cell counts drop, increasing the risk of infection, andred blood cell andplatelet counts may also drop due tobone marrow damage. Chronic eye infections may result from exposure, but blindness is temporary. Long-term effects on the respiratory system includeanosmia (inability to smell),ageusia (inability to taste), inflammation, chronic infections, fibrosis, and cancer. Skin that has been damaged by HN2 can change pigmentation or become scarred, and may eventually develop cancer.[6]
The effect of vesicant (blister) agents in the form ofmustard gas (sulfur mustard, Bis(2-chloroethyl) sulfide) on bone marrow and white blood cells had been known since the First World War.[16] In 1935 several lines of chemical and biological research yielded results that would be explored after the start of the Second World War. The vesicant action of a family of chemicals related to the sulfur mustards, but with nitrogen substituting for sulfur was discovered—the "nitrogen mustards" were born.[17] The particular nitrogen mustard chlormethine (mechlorethamine) was first synthesized.[18] And the action of sulfur mustard on tumors in laboratory animals was investigated for the first time.[19]
After the US entry into the Second World War the nitrogen mustards were candidate chemical warfare agents and research on them was initiated by the Office of Scientific Research and Development (OSRD). The OSRD let contracts to study them to two universities—Yale University and the University of Chicago. Inspired perhaps by the preliminary research in 1935, independently both groups thought to test whether a medically useful differential toxicity between animals and animal tumors existed.[20] The Yale pharmacologists Louis Goodman and Alfred Gilman were the first to conduct a clinical trial, on 27 August 1942, using the agentHN3 (tris(2-chloroethyl)amine) on a patient known as J.D.[21][22][23]
The next year the Chicago group, led by Leon O. Jacobson, conducted trials with HN2 (chlormethine) which was the only agent in this group to see eventual clinical use. Wartime secrecy prevented any of this ground-breaking work on chemotherapy from being published, but papers were released once wartime secrecy ended, in 1946.[24]
Chlormethine is combustible and becomes explosive under extreme conditions. It can react with metals to form gaseous hydrogen.[6]
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