Wikipedia

Semustine

Semustine(1- (2-Chloroethyl)-3-(trans-4-methylcyclohexyl)- 1-nitrosourea, MeCCNU) is an alkylating nitrosourea compound used inchemotherapytreatment of various types of tumours.[1][2]Due to its lipophilic property, semustine can cross the blood-brain barrier for the chemotherapy of brain tumours, where it interferes withDNA replicationin the rapidly-dividing tumour cells.[2] Semustine, just aslomustine,is administered orally. Evidence has been found that treatment with semustine can cause acuteleukaemiaas a delayed effect in very rare cases.[3]

Semustine
Clinical data
ATC code
Identifiers
  • 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea
CAS Number
PubChemCID
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard(EPA)
ECHA InfoCard100.162.271Edit this at Wikidata
Chemical and physical data
FormulaC10H18ClN3O2
Molar mass247.72g·mol−1
3D model (JSmol)
  • CC1CCC(CC1)NC(=O)N(CCCl)N=O
  • InChI=1S/C10H18ClN3O2/c1-8-2-4-9(5-3-8)12-10(15)14(13-16)7-6-11/h8-9H,2-7H2,1H3,(H,12,15)☒N
  • Key:FVLVBPDQNARYJU-UHFFFAOYSA-N☒N
☒NcheckY(what is this?)(verify)

Structure and reactivity

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Semustine (Me-CCNU) is anorganochlorine compoundthat 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.[4][5]

Synthesis

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The synthesis of semustine originates from a systematic synthesis scheme revolving around N-Nitrosourea compounds.[6][7]Phosgene is reacted withAziridineto 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 alongsidecyclohexylamine.For this,TEAcan 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 withsodium nitrite(1) or withtert-Butyl nitrite(2).[8][9]In this synthesis R = H, CH3 or OH. This whole synthesis is shown in Figure 2.

Available forms

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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.[8]

Mechanism of action

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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.[2][10]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[11][12]and inhibiting separation of the DNA strand. By this mechanism, semustine interferes with rapidly proliferating cells and exerts its anti-tumour effects.[10][13]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.[13]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.[10]

Metabolism

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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.[11][14]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.[15] 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.[16]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.[17]These are shown in Figure 4.

Indications

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Nitrosoureas such as semustine frequently cause nausea and vomiting, after admission (4 to 6 hours). The major toxic effects of semustine arethrombocytopeniaandleukopeniacaused by cumulative doses. Secondly the nephrotoxicity and hepatotoxicity of the semustine causepulmonary fibrosisand 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.[18]

Efficacy and side effects

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Efficacy

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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.[19] 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.[20]InChina,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.[21]

Adverse effects

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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.[3]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 ofConnecticutthat these combinations of cancer occur. This could be derived back to the start of the nitrosourea chemotherapy.[3]Providing quantitative evidence that semustine is a carcinogen.[22]For this reason it is also added to IARC group 1 for carcinogenic agents to humans.

Effects on animals

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The described carcinogenicity of semustine to humans has not been found in animals, specifically mice and rats. It is however still acarcinogen.There was an increase found in peritoneal sarcoma and lung tumours, indicating a different toxicity to animals.[19][20]

References

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  1. ^Kramer RA, McMenamin MG, Boyd MR (March 1985). "Differential distribution and covalent binding of two labeled forms of methyl-CCNU in the Fischer 344 rat".Cancer Chemotherapy and Pharmacology.14(2): 150–155.doi:10.1007/BF00434355.PMID3971479.S2CID23111607.
  2. ^abcAgarwal S, Chadha D, Mehrotra R (3 August 2015)."Molecular modeling and spectroscopic studies of semustine binding with DNA and its comparison with lomustine-DNA adduct formation"(PDF).Journal of Biomolecular Structure & Dynamics.33(8): 1653–1668.doi:10.1080/07391102.2014.968874.PMID25350567.S2CID205575020.
  3. ^abcBoice JD, Greene MH, Killen JY, Ellenberg SS, Keehn RJ, McFadden E, et al. (November 1983). "Leukemia and preleukemia after adjuvant treatment of gastrointestinal cancer with semustine (methyl-CCNU)".The New England Journal of Medicine.309(18): 1079–1084.doi:10.1056/NEJM198311033091802.PMID6353233.
  4. ^Suyani H, Zein R, Pardi H, Setiyanto H (2020). "Analysis Method of Anti-Cancer Drug Semustine for Chemotherapy by Cyclic Voltammetry".Rasayan Journal of Chemistry.13(4): 2045–2051.doi:10.31788/RJC.2020.1345845.S2CID226683767.
  5. ^Agarwal S, Chadha D, Mehrotra R (3 August 2015)."Molecular modeling and spectroscopic studies of semustine binding with DNA and its comparison with lomustine-DNA adduct formation"(PDF).Journal of Biomolecular Structure & Dynamics.33(8): 1653–1668.doi:10.1080/07391102.2014.968874.PMID25350567.S2CID205575020.
  6. ^Johnston TP, Mccaleb GS, Montgomery JA (November 1963). "The Synthesis of Antineoplastic Agents. XXXII. N-Nitrosoureas.1 I".Journal of Medicinal Chemistry.6(6): 669–681.doi:10.1021/jm00342a010.PMID14184923.
  7. ^Lednicer D (17 October 2007).The Organic Chemistry of Drug Synthesis.doi:10.1002/9780470180679.ISBN9780470107508.
  8. ^abJaman Z, Sobreira TJ, Mufti A, Ferreira CR, Cooks RG, Thompson DH (15 March 2019). "Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions".Organic Process Research & Development.23(3): 334–341.doi:10.1021/acs.oprd.8b00387.S2CID104459077.
  9. ^Dirikolu L, Chakkath T, Fan T, Mente NR (1 November 2009)."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 of Analytical Toxicology.33(9): 595–603.doi:10.1093/jat/33.9.595.PMID20040134.
  10. ^abcShiri F, Norouzibazaz M, Yari A, Taherpour AA (October 2018). "A DFT study of both the hydrolytic degradation and protonation of semustine in variation conditions of pH and interaction of drug with DNA nucleobases".Structural Chemistry.29(5): 1465–1474.doi:10.1007/s11224-018-1130-4.S2CID103682718.
  11. ^abCentre international de recherche sur le cancer (2012).A Review of Human Carcinogens: Chemical Agents and Related Occupations.IARC Monographs. Vol. 100 - Part F.
  12. ^Occupational Exposures in Petroleum Refining - Crude Oil and Major Petroleum Fuels (1989).IARC Monographs. Vol. 45. Lyons: CIR.
  13. ^abScholar E (2007). "Alkylating Agents".XPharm: The Comprehensive Pharmacology Reference:1–4.doi:10.1016/B978-008055232-3.61034-7.ISBN9780080552323.
  14. ^van Mil JW (October 2011). Sweetman SC (ed.)."The Martindale, the complete dug reference, 37th edn: The Pharmaceutical Press, 2011, ISBN 978-0-85369-933-0".International Journal of Clinical Pharmacy.33(5): 876.doi:10.1007/s11096-011-9543-9.S2CID43827523.
  15. ^Pratt WB (1994).The anticancer drugs(2nd ed.). New York: Oxford University Press.
  16. ^Turci R (2005). "Semustine".Encyclopedia of Toxicology:776–779.doi:10.1016/B0-12-369400-0/00218-0.ISBN9780123694003.
  17. ^Kohlhepp SJ, May HE, Reed DJ (1 March 1981)."Urinary metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea".Drug Metabolism and Disposition.9(2): 135–141.PMID6113112.
  18. ^Ries F, Klastersky J (November 1986). "Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity".American Journal of Kidney Diseases.8(5): 368–379.doi:10.1016/S0272-6386(86)80112-3.PMID3538860.
  19. ^abLiu HT, Xue SB, Zhang HQ, Tang J, Zhang YM, Tian ZJ, et al. (1979)."[A preliminary study of 57Ca-zhengguangmycin distribution in tumor-bearing mice and in clinical scanning (author's transl)]".Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology].1(2): 106–112.PMID95441.
  20. ^abMcMahon LJ, Jones SE, Durie BG, Salmon SE (November 1975). "Combination chemotherapy with methyl-CCNU (NSC-95441), cyclophosphamide (NSC-26271), vincristine (NSC-67574), methotrexate (NSC-740), and bleomycin (NSC-125066) in advanced bronchogenic carcinoma".Cancer Letters.1(2): 97–102.doi:10.1016/S0304-3835(75)95630-X.PMID65213.
  21. ^Guo Y, Lu JJ, Ma X, Wang B, Hong X, Li X, Li J (January 2008). "Combined chemoradiation for the management of nasal natural killer (NK)/T-cell lymphoma: elucidating the significance of systemic chemotherapy".Oral Oncology.44(1): 23–30.doi:10.1016/j.oraloncology.2006.11.020.PMID17306611.
  22. ^Boice JD, Greene MH, Killen JY, Ellenberg SS, Fraumeni JF, Keehn RJ, et al. (January 1986). "Leukemia after adjuvant chemotherapy with semustine (methyl-CCNU)--evidence of a dose-response effect".The New England Journal of Medicine.314(2): 119–120.doi:10.1056/NEJM198601093140214.PMID3941685.
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