Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Chlormethine: Difference between pages

{{distinguish|Chloromethane}}

{{chembox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 480478174

| ImageFile = Chlormethine.svg

| ImageAlt = Skeletal formula of chlormethine

| ImageFile1 = Mechlorethamine 3D spacefill.png

| ImageSize1 = 180

| ImageAlt1 = Space-filling model of the chlormethine molecule

| IUPACName = 2-Chloro-''N''-(2-chloroethyl)-''N''-methylethanamine

| OtherNames = {{Unbulleted list

| Bis(2-chloroethyl)(methyl)amine

| mechlorethamine

| mustine

| HN-2

| ''Ledaga''<ref name="Ledaga APM summary" /><ref name="Ledaga EPAR" />

}}

|Section1={{Chembox Identifiers

| CASNo = 51-75-2

| CASNo_Ref = {{cascite|correct|CAS}}

| PubChem = 4033

| ChemSpiderID = 3893

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| UNII = 50D9XSG0VR

| UNII_Ref = {{fdacite|correct|FDA}}

| EINECS = 200-120-5

| DrugBank = DB00888

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| KEGG = D0767

| KEGG_Ref = {{keggcite|changed|kegg}}

| MeSHName = Mechlorethamine

| ChEBI = 28925

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 427

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| SMILES = CN(CCCl)CCCl

| StdInChI = 1S/C5H11Cl2N/c1-8(4-2-6)5-3-7/h2-5H2,1H3

| StdInChI_Ref = {{chemspidercite|correct|chemspider}}

| StdInChIKey = HAWPXGHAZFHHAD-UHFFFAOYSA-N

| StdInChIKey_Ref = {{chemspidercite|correct|chemspider}}

| RTECS = IA1750000

| UNNumber = 2810

|Section2={{Chembox Properties

| C=5 | H=11 | Cl=2 | N=1

| Appearance = Colorless liquid

| Odor = Fishy, ammoniacal

| LogP = 0.91

|Section6 = {{Chembox Pharmacology

| Pharmacology_ref =

| ATCCode_prefix = D08

| ATCCode_suffix = AX04

| ATC_Supplemental = {{ATC|L01|AA05}}

| ATCvet =

| Licence_EU =

| INN =

| INN_EMA =

| Licence_US =

| Legal_status = Rx-only

| Legal_AU = S4

| Legal_AU_comment = <ref name="Ledaga APM summary">{{cite web | title=Ledaga | website=Therapeutic Goods Administration (TGA) | date=30 June 2021 | url=https://www.tga.gov.au/apm-summary/ledaga | access-date=5 September 2021 | archive-date=5 September 2021 | archive-url=https://web.archive.org/web/20210905221529/https://www.tga.gov.au/apm-summary/ledaga | url-status=live }}</ref>

| Legal_CA = Rx-only

| Legal_CA_comment = <ref>{{cite web | title=Health product highlights 2021: Annexes of products approved in 2021 | website=[[Health Canada]] | date=3 August 2022 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-product-highlights-2021/appendices.html | access-date=25 March 2024}}</ref>

| Legal_NZ =

| Legal_NZ_comment =

| Legal_UK =

| Legal_UK_comment =

| Legal_US =

| Legal_US_comment =

| Legal_EU = Rx-only

| Legal_EU_comment = <ref name="Ledaga EPAR">{{cite web | title=Ledaga EPAR | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/ledaga | access-date=5 September 2021 | archive-date=5 September 2021 | archive-url=https://web.archive.org/web/20210905221530/https://www.ema.europa.eu/en/medicines/human/EPAR/ledaga | url-status=live }}</ref>

| Legal_UN =

| Legal_UN_comment =

| Pregnancy_category =

| Pregnancy_AU = B3

| Pregnancy_AU_comment = <ref name="Ledaga APM summary" />

| Dependence_liability =

| AdminRoutes = {{unbulleted list|Intracavitary|Intrapericardial|Intravenous|Topical}}

| Bioavail =

| ProteinBound =

| Metabolism =

| Metabolites =

| OnsetOfAction =

| HalfLife = <1 minute

| DurationOfAction =

| Excretion = 50% (Kidney)

}}

|Section8={{Chembox Related

| OtherFunction_label = amines

| OtherFunction = {{unbulleted list|[[Dimethylamine]]|[[Trimethylamine]]|[[n-Nitrosodimethylamine|''N''-Nitrosodimethylamine]]|[[Diethylamine]]|[[Triethylamine]]|[[Diisopropylamine]]|[[Dimethylaminopropylamine]]|[[Diethylenetriamine]]|[[n,N-Diisopropylethylamine|''N'',''N''-Diisopropylethylamine]]|[[Triisopropylamine]]|[[Tris(2-aminoethyl)amine]]|[[HN1 (nitrogen mustard)]]|[[HN3 (nitrogen mustard)]]}}

| OtherCompounds =

'''Chlormethine''' ([[International Nonproprietary Name|INN]], [[British Approved Name|BAN]]), also known as '''mechlorethamine''' ([[United States Adopted Name|USAN]], [[United States Pharmacopeia|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 agent]]s, a group of [[cancer|anticancer]] chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base [[guanine]]. As the chemical is a [[blister agent]], its use is strongly restricted within the [[Chemical Weapons Convention]] where it is classified as a [[List of Schedule 1 substances (CWC)|Schedule 1 substance]].

Mechlorethamine belongs to the group of [[nitrogen mustard]] [[alkylating antineoplastic agent|alkylating agents]].<ref name="pmid10746948">{{cite journal |vauthors=Rappeneau S, Baeza-Squiban A, Jeulin C, Marano F |title=Protection from cytotoxic effects induced by the nitrogen mustard mechlorethamine on human bronchial epithelial cells in vitro |journal=Toxicol. Sci. |volume=54 |issue=1 |pages=212–21 |date=March 2000 |pmid=10746948 |doi= 10.1093/toxsci/54.1.212|doi-access=free }}</ref><ref>{{cite book | chapter=Chapter 3: Principles of Oncologic Pharmacotherapy | title=Cancer Management: A Multidisciplinary Approach | year=2010 | url=http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 | archive-url=https://web.archive.org/web/20090515221337/http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 | archive-date=15 May 2009 | url-status=dead | access-date=8 October 2023}}</ref><ref name=":0">{{Cite web|url=https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750011.html|title=CDC - The Emergency Response Safety and Health Database: Blister Agent: NITROGEN MUSTARD HN-2 - NIOSH|website=U.S. [[Centers for Disease Control and Prevention]] (CDC) |access-date=2016-04-20|archive-date=2019-06-28|archive-url=https://web.archive.org/web/20190628200614/https://www.cdc.gov/NIOSH/ershdb/EmergencyResponseCard_29750011.html|url-status=live}}</ref>

==Uses==

It has been derivatized into the [[estrogen]] analogue [[estramustine phosphate]], used to treat [[prostate cancer]]. It can also be used in [[chemical warfare]] where it has the code-name '''HN2'''. This chemical is a form of nitrogen [[mustard gas]] and a powerful [[vesicant]]. Historically, some uses of mechlorethamine have included lymphoid malignancies such as Hodgkin's disease, lymphosarcoma, chronic myelocytic leukemia, polycythemia vera, and bronchogenic carcinoma <ref>{{Cite journal | pmid = 8085692| year = 1994| last1 = Bunn Jr| first1 = P. A.| title = Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and the Sézary syndrome)| journal = Annals of Internal Medicine| volume = 121| issue = 8| pages = 592–602| last2 = Hoffman| first2 = S. J.| last3 = Norris| first3 = D| last4 = Golitz| first4 = L. E.| last5 = Aeling| first5 = J. L.| doi=10.7326/0003-4819-121-8-199410150-00007| s2cid = 22909007}}</ref> Mechlorethamine is often administered intravenously,<ref>Medline (2012). Mechlorethamine. Retrieved from https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682223.html {{Webarchive|url=https://web.archive.org/web/20160705113033/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682223.html |date=2016-07-05 }}</ref> 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.<ref>Lindahl LM, Fenger-Gron M, Iversen L. Topical nitrogen mustard therapy in patients with mycosis fungoides or parapsoriasis. J Eur Acad Dermatol Venereol. 2013 Feb;27(2):163-8.</ref><ref>Galper SL, Smith BD, Wilson LD. Diagnosis and management of mycosis fungoides. Oncology (Williston Park). 2010 May;24(6):491-501.</ref><ref>Lessin SR, Duvic M, Guitart J, Pandya AG, Strober BE, Olsen EA, Hull CM, Knobler EH, Rook AH, Kim EJ, Naylor MF, Adelson DM, Kimball AB, Wood GS, Sundram U, Wu H, Kim YH. Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol. 2013 Jan;149(1):25-32.</ref>

Another use of chlormethine is in the synthesis of [[pethidine]] (meperidine).<ref>{{cite journal|last1=McErlane|first1=KM|last2=Wood|first2=RJ|last3=Matsui|first3=F|last4=Lovering|first4=EG|title=Impurities in Drugs II: Meperidine and Its Formulations|journal=Journal of Pharmaceutical Sciences|date=July 1978|volume=67|issue=7|pages=958–961|doi=10.1002/jps.2600670723|pmid=660515}}</ref>

==Side effects and toxicity==

Mechlorethamine is a highly toxic medication, especially for women who are pregnant, breastfeeding, or of childbearing age.<ref>Recordati Rare Diseases Inc. (2013). Mustargen Package Insert. Retrieved from https://www.drugs.com/pro/mustargen.html {{Webarchive|url=https://web.archive.org/web/20180920170811/https://www.drugs.com/pro/mustargen.html |date=2018-09-20 }}</ref><ref>Actelion Pharmaceuticals Ltd. (2013) Valchlor Package Insert. Retrieved from http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202317lbl.pdf {{Webarchive|url=https://web.archive.org/web/20210328134300/https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202317lbl.pdf |date=2021-03-28 }}</ref> At high enough levels, exposure can be fatal.<ref name=":0" />

The adverse effects of mechlorethamine depend on the formulation.<ref>[https://www.drugs.com/pro/mustargen.html Mustargen] {{Webarchive|url=https://web.archive.org/web/20180920170811/https://www.drugs.com/pro/mustargen.html |date=2018-09-20 }} and [http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202317lbl.pdf Valchlor] {{Webarchive|url=https://web.archive.org/web/20210328134300/https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202317lbl.pdf |date=2021-03-28 }}</ref> 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.<ref name=":0" />

Symptoms of toxic exposure to HN-2 vary based on the route of exposure. Eye exposure causes [[Tears|lacrimation]] (tear production), burning, irritation, itching, a feeling of grittiness or dryness, [[blepharospasm]] (spasms of the eyelid), and [[miosis]] (pinpoint pupils). More severe cases cause [[edema]] (swelling from fluid accumulation) in the eyelids, [[photophobia]] (extreme sensitivity to light), severe pain, [[corneal ulcer]]ation, and blindness.<ref name=":0" />

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 include [[rhinorrhea]] (runny nose), [[Nosebleed|epistaxis]] (nosebleed), toneless voice, sneezing, barking cough, and [[dyspnea]] (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.<ref name=":0" />

Skin exposure mainly causes [[erythema]] (redness) and [[Blister|vesication]] (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.<ref name=":0" />

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.<ref name=":0" />

Long-term effects of acute or chronic chlormethine exposure are caused by damage to the [[immune system]]. [[White blood cell]] counts drop, increasing the risk of infection, and [[red blood cell]] and [[platelet]] counts may also drop due to [[bone marrow]] damage. Chronic eye infections may result from exposure, but blindness is temporary. Long-term effects on the respiratory system include [[anosmia]] (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.<ref name=":0" />

==History==

The effect of vesicant (blister) agents in the form of [[mustard gas]] (sulfur mustard, Bis(2-chloroethyl) sulfide) on bone marrow and white blood cells had been known since the First World War.<ref>{{cite journal | vauthors = Krumbhaar EB, Krumbhaar HD | url = https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC2104437&blobtype=pdf | title = The blood and bone marrow in yellow cross gas (mustard gas) poisoning: changes produced in the bone marrow of fatal cases | journal = J Med Res | year = 1919 | volume = 40 | pages = 497–508 | doi = 10.1016/0002-9610(63)90232-0 | issue = 5 | pmid = 13947966 | access-date = 2018-10-14 | archive-date = 2020-02-10 | archive-url = https://web.archive.org/web/20200210044110/http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC2104437&blobtype=pdf | url-status = live }}</ref> 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.<ref>{{cite journal | author = Ward, Kyle | title = The Chlorinated Ethylamines — A New Type of Vesicant | journal = J. Am. Chem. Soc. | year = 1935 | volume = 57 | pages = 914–916 | doi = 10.1021/ja01308a041 | issue = 5}}</ref> The particular nitrogen mustard chlormethine (mechlorethamine) was first synthesized.<ref>{{cite journal | author = V. Prelog, V. Štěpán | title = Nouvele synthèse des pipérazines N-monoalcoylées (VIIième communication sur les bis-[β-halogénoéthyl]-amines) | journal = Collection of Czechoslovak Chemical Communications | year = 1935 | volume = 7 | pages = 93–102 | doi = 10.1135/cccc19350093}}</ref> And the action of sulfur mustard on tumors in laboratory animals was investigated for the first time.<ref>{{cite journal | author = Berenblum I. | title = Experimental inhibition of tumor induction by mustard gas and other compounds | journal = Journal of Pathology and Bacteriology | year = 1935 | volume = 40 | issue = 3 | pages = 549–558 | doi = 10.1002/path.1700400312}}</ref>

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.<ref>{{cite journal | author = Einhorn, J. | title = Nitrogen mustard: the origin of chemotherapy for cancer | journal = Int J Radiat Oncol Biol Phys | year = 1985 | volume = 11 | pages = 1375–1378 | doi = 10.1016/0360-3016(85)90254-8 | pmid = 3891698 | issue = 7 }}</ref> The Yale pharmacologists Louis Goodman and Alfred Gilman were the first to conduct a clinical trial, on 27 August 1942, using the agent [[HN3 (nitrogen mustard)|HN3]] (tris(2-chloroethyl)amine) on a patient known as J.D.<ref>{{cite journal | author = Alfred Gilman, Frederick S. Philips | title = The Biological Actions and Therapeutic Applications of the B-Chloroethyl Amines and Sulfides | journal = Science | year = 1946 | volume = 103 | pages = 409–436 | doi = 10.1126/science.103.2675.409 | pmid = 17751251 | bibcode = 1946Sci...103..409G | issue = 2675}}</ref><ref>{{cite journal | author = Gilman, Alfred | title = The initial clinical trial of nitrogen mustard | journal = Am J Surg | year = 1963 | volume = 105 | pages = 574–578 | pmid = 13947966 | doi = 10.1016/0002-9610(63)90232-0 | issue = 5}}</ref><ref>{{cite journal | author = Fenn, John E.|display-authors=et al | title = First Use of Intravenous Chemotherapy Cancer Treatment: Rectifying the Record | journal = Journal of the American College of Surgeons | year = 2011 | volume = 212 | pages = 413–417 | doi = 10.1016/j.jamcollsurg.2010.10.018 | pmid = 21247779 | issue = 3 }}</ref>

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.<ref>{{cite journal | author = Jacobson L.O., Spurr C.L., Barron E., Smith T., Lushbaugh C., Dick G.F. | title = Nitrogen Mustard Therapy: Studies on the Effect of Methyl-Bis (Beta-Chloroethyl) Amine Hydrochloride on Neoplastic Diseases and Allied Disorders of the Hemopoietic System | journal = JAMA | year = 1946 | volume = 132 | pages = 263–271 | doi = 10.1001/jama.1946.02870400011003 | pmid = 20997209 | issue = 2675}}</ref>

== Chemistry ==

Chlormethine is combustible and becomes explosive under extreme conditions. It can react with metals to form gaseous hydrogen.<ref name=":0" />

==References==

{{Reflist}}

{{Chemical agents}}

{{Chemotherapeutic agents}}

{{Nitrogen mustards}}

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[[Category:Amines]]

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