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{{Short description|Chemical compound}}
{{Infobox drug
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| image = Semustine.
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| pregnancy_US = <!-- A / B
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| ChEBI = 6863
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| C=10 | H=18 | Cl=1 | N=3 | O=2
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▲| smiles = CC1CCC(NC(=O)N(C=O)CCCl)CC1
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▲| StdInChIKey = VZOOXPNKNMPOFU-UHFFFAOYSA-N
}}
'''Semustine''' (1- (2-Chloroethyl)-3-(trans-4-methylcyclohexyl)- 1-nitrosourea, MeCCNU) is an alkylating nitrosourea compound used in [[chemotherapy]] treatment of various types of tumours.<ref name="Kramer">{{cite journal | vauthors = Kramer RA, McMenamin MG, Boyd MR | title = Differential distribution and covalent binding of two labeled forms of methyl-CCNU in the Fischer 344 rat | journal = Cancer Chemotherapy and Pharmacology | volume = 14 | issue = 2 | pages = 150–155 | date = March 1985 | pmid = 3971479 | doi = 10.1007/BF00434355 | s2cid = 23111607 }}</ref><ref name="Agarwal">{{cite journal | vauthors = Agarwal S, Chadha D, Mehrotra R | title = Molecular modeling and spectroscopic studies of semustine binding with DNA and its comparison with lomustine-DNA adduct formation | journal = Journal of Biomolecular Structure & Dynamics | volume = 33 | issue = 8 | pages = 1653–1668 | date = 3 August 2015 | pmid = 25350567 | doi = 10.1080/07391102.2014.968874 | s2cid = 205575020 | url = http://npl.csircentral.net/1906/1/213.pdf }}</ref> Due to its lipophilic property, semustine can cross the blood-brain barrier for the chemotherapy of brain tumours, where it interferes with [[DNA replication]] in the rapidly-dividing tumour cells.<ref name="Agarwal"/>
Semustine, just as [[lomustine]], is administered orally.
Evidence has been found that treatment with semustine can cause acute [[Leukemia|leukaemia]] as a delayed effect in very rare cases.<ref name="Boice">{{cite journal | vauthors = Boice JD, Greene MH, Killen JY, Ellenberg SS, Keehn RJ, McFadden E, Chen TT, Fraumeni JF | display-authors = 6 | title = Leukemia and preleukemia after adjuvant treatment of gastrointestinal cancer with semustine (methyl-CCNU) | journal = The New England Journal of Medicine | volume = 309 | issue = 18 | pages = 1079–1084 | date = November 1983 | pmid = 6353233 | doi = 10.1056/NEJM198311033091802 }}</ref>
==Synthesis==▼
== Structure and reactivity ==
==References==▼
Semustine (Me-CCNU) is an [[organochlorine compound]] that is urea in which the two hydrogens on one of the amino groups are replaced by nitroso and 2-chloroetyl groups and one hydrogen from the other amino group is replaced by a 4-methylcyclohexcyl group. Semustine is also known as a 4-methyl derivative of lomustine.<ref name="Suyani">{{cite journal | vauthors = Suyani H, Zein R, Pardi H, Setiyanto H |title= Analysis Method of Anti-Cancer Drug Semustine for Chemotherapy by Cyclic Voltammetry |journal=Rasayan Journal of Chemistry |date=2020 |volume=13 |issue=4 |pages=2045–2051 |doi=10.31788/RJC.2020.1345845|s2cid= 226683767 }}</ref><ref name="Chadha">{{cite journal | vauthors = Agarwal S, Chadha D, Mehrotra R | title = Molecular modeling and spectroscopic studies of semustine binding with DNA and its comparison with lomustine-DNA adduct formation | journal = Journal of Biomolecular Structure & Dynamics | volume = 33 | issue = 8 | pages = 1653–1668 | date = 3 August 2015 | pmid = 25350567 | doi = 10.1080/07391102.2014.968874 | s2cid = 205575020 | url = http://npl.csircentral.net/1906/1/213.pdf }}</ref>
▲== Synthesis ==
The synthesis of semustine originates from a systematic synthesis scheme revolving around N-Nitrosourea compounds.<ref name="Johnston">{{cite journal | vauthors = Johnston TP, Mccaleb GS, Montgomery JA | title = The Synthesis of Antineoplastic Agents. XXXII. N-Nitrosoureas.1 I | journal = Journal of Medicinal Chemistry | volume = 6 | issue = 6 | pages = 669–681 | date = November 1963 | pmid = 14184923 | doi = 10.1021/jm00342a010 }}</ref><ref name="Lednicer">{{cite book | vauthors = Lednicer D |title=The Organic Chemistry of Drug Synthesis |date=17 October 2007 |doi=10.1002/9780470180679|isbn=9780470107508 }}</ref> Phosgene is reacted with [[Aziridines|Aziridine]] to produce the chemical intermediate di(aziridin-1-yl) methanone. This reacts with the subsequently released HCl from the production of the intermediate to open the Aziridine rings and it will form 1,3-bis(2-chloroethyl)-urea. The next step is to nitrosate this compound with the sodium nitrite in formic acid. This will give one of the nitrogen’s a nitroso functional group. With this step carmustine (BCNU), another medication used for chemotherapy, is formed. BCNU is subsequently decomposed in the presence of 4-Methylcyclohexylamine. The aliphatic amine is in two equivalents present during the decomposition. During the decomposition, the compound loses its nitroso group and only one methyl cyclohexyl group will be found on the compound. The final step is to repeat the nitrosation of the compound under the same conditions and Semustine (Me-CCNU) is synthesised. This whole synthesis is shown in Figure 1.
More recent studies suggest using 1-chloro-2-isocyanatoethyl as a starting material alongside [[cyclohexylamine]]. For this, [[Triethylamine|TEA]] can be used as a catalyst to get to the same final step as the previously mentioned synthesis route. In this final step, the nitrosation can be done again with [[sodium nitrite]] (1) or with [[tert-Butyl nitrite]] (2).<ref name="Jaman">{{cite journal | vauthors = Jaman Z, Sobreira TJ, Mufti A, Ferreira CR, Cooks RG, Thompson DH |title=Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions |journal=Organic Process Research & Development |date=15 March 2019 |volume=23 |issue=3 |pages=334–341 |doi=10.1021/acs.oprd.8b00387|s2cid=104459077 }}</ref><ref name="Dirikolu">{{cite journal | vauthors = Dirikolu L, Chakkath T, Fan T, Mente NR | title = Synthesis of trans- and cis-4'-hydroxylomustine and development of validated analytical method for lomustine and trans- and cis-4'-hydroxylomustine in canine plasma | journal = Journal of Analytical Toxicology | volume = 33 | issue = 9 | pages = 595–603 | date = 1 November 2009 | pmid = 20040134 | doi = 10.1093/jat/33.9.595 | doi-access = free }}</ref> In this synthesis R = H, CH3 or OH. This whole synthesis is shown in Figure 2.
== Available forms ==
Since the synthesis yields a stable substance, this compound is usually delivered as pure substance and not as a salt. When supplied as medicine, the most common forms of administration are pills with a range from 3.0 to 100 mg semustine per pill.<ref name="Jaman" />
== Mechanism of action ==
DNA is the most significant part of the cell, performing the most important processes, replication, and transcription. These processes and DNA itself can be targeted with small molecules or ligands with possible antitumor activity, resulting in prevention of continuous growth and proliferating of cancer cells.<ref name="Agarwal" /><ref name="Shiri">{{cite journal | vauthors = Shiri F, Norouzibazaz M, Yari A, Taherpour AA |title=A DFT study of both the hydrolytic degradation and protonation of semustine in variation conditions of pH and interaction of drug with DNA nucleobases |journal=Structural Chemistry |date=October 2018 |volume=29 |issue=5 |pages=1465–1474 |doi=10.1007/s11224-018-1130-4|s2cid=103682718 }}</ref> The common property of alkylating agents, including semustine, is their capacity to become very strong electrophiles through the formation of (chloro-) carbonium ion intermediates, which are products of the hydrolysis of the semustine drug. This reaction yields covalent cross-links between various nucleophilic DNA bases by alkylation, causing denaturation of the double helix <ref name="Centre">{{cite book | author = Centre international de recherche sur le cancer | date = 2012 | title = A Review of Human Carcinogens: Chemical Agents and Related Occupations. | series = IARC Monographs | volume = 100 - Part F}}</ref><ref>{{cite book | title = Occupational Exposures in Petroleum Refining - Crude Oil and Major Petroleum Fuels (1989) | series = IARC Monographs | volume = 45 | location = Lyons | publisher = CIR }}</ref> and inhibiting separation of the DNA strand. By this mechanism, semustine interferes with rapidly proliferating cells and exerts its anti-tumour effects.<ref name="Shiri" /><ref name="Scholar">{{cite journal | vauthors = Scholar E |title=Alkylating Agents |journal=XPharm: The Comprehensive Pharmacology Reference |date=2007 |pages=1–4 |doi=10.1016/B978-008055232-3.61034-7|isbn=9780080552323 }}</ref> Targets of the interstrand cross-link forming are specifically the N-7 of guanine, O-6 of adenine and other sites on the purine bases.<ref name="Scholar" /> This is depicted in Figure 3.
The electrophilic property of semustine increases under acidic conditions, which makes the nucleophilic attack occur much faster. In general, acidic pH conditions cause a significant increase in the reaction rate of the semustine drug.<ref name="Shiri" />
== Metabolism ==
After oral administration and absorption from the gastrointestinal tract, semustine undergoes rapid chemical decomposition and oxidative metabolism. Due to the lipophilic nature of semustine, the distribution is quickly across the tissue.<ref name="Centre" /><ref name="Mil">{{cite journal | vauthors = van Mil JW | veditors = Sweetman SC |title=The Martindale, the complete dug reference, 37th edn: The Pharmaceutical Press, 2011, ISBN 978-0-85369-933-0 |journal=International Journal of Clinical Pharmacy |date=October 2011 |volume=33 |issue=5 |pages=876 |doi=10.1007/s11096-011-9543-9| s2cid = 43827523 |doi-access=free }}</ref> Semustine is metabolised by the cytochrome P450 (CYP) mono-oxygenase system on the cyclohexyl ring carbons and the 2-chloroethyl sidechain resulting hydroxylated metabolites, which remains alkylating and anti-tumour active. Most of the biological effect is due to the generation of the chloroethyl carbonium ion from the ring hydroxylated metabolite. Ring hydroxylation occurs during the “first pass” through the gut wall and liver.<ref name="Pratt">{{cite book | vauthors = Pratt WB |title=The anticancer drugs |date=1994 |publisher=Oxford University Press |location=New York |edition=2nd}}</ref>
The metabolites and decomposition products are excreted by the kidneys into the urine. Up to 60% of the dose is excreted by urine within 48 hours.<ref name="Turci">{{cite journal | vauthors = Turci R |title=Semustine |journal=Encyclopedia of Toxicology |date=2005 |pages=776–779 |doi=10.1016/B0-12-369400-0/00218-0|isbn=9780123694003 }}</ref> The decomposition products present in the urine are cis-3-hydroxy-trans-4-methylcyclohexylamine, trans-4-methylcyclohexylamine, trans-4-hydroxymethylcyclohexylamine and trans-3-hydroxy-trans-4-methyl-cyclohexylamine.<ref name="Kohlhepp">{{cite journal | vauthors = Kohlhepp SJ, May HE, Reed DJ | title = Urinary metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea | journal = Drug Metabolism and Disposition | volume = 9 | issue = 2 | pages = 135–141 | date = 1 March 1981 | pmid = 6113112 | url = https://dmd.aspetjournals.org/content/9/2/135 }}</ref> These are shown in Figure 4.
== Indications ==
Nitrosoureas such as semustine frequently cause nausea and vomiting, after admission (4 to 6 hours). The major toxic effects of semustine are [[thrombocytopenia]] and [[leukopenia]] caused by cumulative doses. Secondly the nephrotoxicity and hepatotoxicity of the semustine cause [[pulmonary fibrosis]] and renal dysfunction. Semustine nephrotoxicity is cumulative, the cumulative dose at which nephrotoxicity is likely to occur has been estimated to be near 2,000 mg/m2. This problem generally appears only in patients being treated for more than 1 year, which requires a prolonged survival time.<ref name="Ries">{{cite journal | vauthors = Ries F, Klastersky J | title = Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity | journal = American Journal of Kidney Diseases | volume = 8 | issue = 5 | pages = 368–379 | date = November 1986 | pmid = 3538860 | doi = 10.1016/S0272-6386(86)80112-3 }}</ref>
== Efficacy and side effects ==
=== Efficacy ===
Semustine was used to treat several different types of cancers. The main one was L1210 leukaemia and Hodgkin lymphoma. Other types are metastatic brain tumours, Lewis lung tumours, cancers of the digestive tract, lymphoma, malignant melanoma, and epidermoid carcinoma of the lung.<ref name="Liu">{{cite journal | vauthors = Liu HT, Xue SB, Zhang HQ, Tang J, Zhang YM, Tian ZJ, Wang JX, Meng FY | display-authors = 6 | title = [A preliminary study of 57Ca-zhengguangmycin distribution in tumor-bearing mice and in clinical scanning (author's transl)] | journal = Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology] | volume = 1 | issue = 2 | pages = 106–112 | date = 1979 | pmid = 95441 | url = https://pubmed.ncbi.nlm.nih.gov/95441/ }}</ref>
It has however not shown desired results as an antineoplastic drug and thus has never been approved for it. Combinations with other drugs have also been done in the 70’s but have not shown more beneficial results.<ref name="McMahon">{{cite journal | vauthors = McMahon LJ, Jones SE, Durie BG, Salmon SE | title = Combination chemotherapy with methyl-CCNU (NSC-95441), cyclophosphamide (NSC-26271), vincristine (NSC-67574), methotrexate (NSC-740), and bleomycin (NSC-125066) in advanced bronchogenic carcinoma | journal = Cancer Letters | volume = 1 | issue = 2 | pages = 97–102 | date = November 1975 | pmid = 65213 | doi = 10.1016/S0304-3835(75)95630-X }}</ref> In [[China]], research is still done on the compound. These however also state the need for further investigation and possible different combinations of antineoplastic drugs to get a higher rate of complete response and overall survival after treatment.<ref name="Guo">{{cite journal | vauthors = Guo Y, Lu JJ, Ma X, Wang B, Hong X, Li X, Li J | title = Combined chemoradiation for the management of nasal natural killer (NK)/T-cell lymphoma: elucidating the significance of systemic chemotherapy | journal = Oral Oncology | volume = 44 | issue = 1 | pages = 23–30 | date = January 2008 | pmid = 17306611 | doi = 10.1016/j.oraloncology.2006.11.020 }}</ref>
=== Adverse effects ===
During the trials of semustine, sufficient evidence was found that semustine is a carcinogen. During a trail of 2067 patients, 14 cases of acute leukaemia were found. This was combined with a roughly 4% chance to acquire leukaemia disorder within six years.<ref name="Boice" /> This trail was done on patients with gastrointestinal cancer and before the use of this antineoplastic drug, there were no recorded cases in the medical history of [[Connecticut]] that these combinations of cancer occur. This could be derived back to the start of the nitrosourea chemotherapy.<ref name="Boice" /> Providing quantitative evidence that semustine is a carcinogen.<ref name="Leukemia">{{cite journal | vauthors = Boice JD, Greene MH, Killen JY, Ellenberg SS, Fraumeni JF, Keehn RJ, McFadden E, Chen TT, Stablein D | display-authors = 6 | title = Leukemia after adjuvant chemotherapy with semustine (methyl-CCNU)--evidence of a dose-response effect | journal = The New England Journal of Medicine | volume = 314 | issue = 2 | pages = 119–120 | date = January 1986 | pmid = 3941685 | doi = 10.1056/NEJM198601093140214 }}</ref> For this reason it is also added to IARC group 1 for carcinogenic agents to humans.
== Effects on animals ==
The described carcinogenicity of semustine to humans has not been found in animals, specifically mice and rats. It is however still a [[carcinogen]]. There was an increase found in peritoneal sarcoma and lung tumours, indicating a different toxicity to animals.<ref name="Liu" /><ref name="McMahon" />
▲== References ==
{{reflist}}
{{Chemotherapeutic agents}}
[[Category:Nitrosamines]]▼
[[Category:Ureas]]▼
[[Category:Nitrosoureas]]▼
[[Category:Alkylating antineoplastic agents]]
[[Category:IARC Group 1 carcinogens]]
▲[[Category:Nitrosamines]]
[[Category:Organochlorides]]
[[Category:Withdrawn drugs]]
[[Category:Chloroethyl compounds]]
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