Semustine
Clinical data
ATC code
Identifiers
  • 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.162.271
Chemical and physical data
FormulaC10H18ClN3O2
Molar mass247.72 g·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)

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.[1][2] 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.[2] Semustine, just as lomustine, is administered orally. Evidence has been found that treatment with semustine can cause acute leukaemia as a delayed effect in very rare cases.[3]

Structure and reactivity

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.[4][5]

Synthesis

The synthesis of semustine originates from a systematic synthesis scheme revolving around N-Nitrosourea compounds.[6][7] Phosgene is reacted with 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, 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).[8][9] 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.[8]

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.[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

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

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.[18]

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.[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] 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.[21]

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.[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 of Connecticut that 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

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.[19][20]

References

  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. PMID 3971479. S2CID 23111607.
  2. 1 2 3 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. PMID 25350567. S2CID 205575020.
  3. 1 2 3 Boice 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. PMID 6353233.
  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. S2CID 226683767.
  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. PMID 25350567. S2CID 205575020.
  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. PMID 14184923.
  7. ↑ Lednicer D (17 October 2007). The Organic Chemistry of Drug Synthesis. doi:10.1002/9780470180679. ISBN 9780470107508.
  8. 1 2 Jaman 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. S2CID 104459077.
  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. PMID 20040134.
  10. 1 2 3 Shiri 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. S2CID 103682718.
  11. 1 2 Centre 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. 1 2 Scholar E (2007). "Alkylating Agents". XPharm: The Comprehensive Pharmacology Reference: 1–4. doi:10.1016/B978-008055232-3.61034-7. ISBN 9780080552323.
  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. S2CID 43827523.
  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. ISBN 9780123694003.
  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. PMID 6113112.
  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. PMID 3538860.
  19. 1 2 Liu 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. PMID 95441.
  20. 1 2 McMahon 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. PMID 65213.
  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. PMID 17306611.
  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. PMID 3941685.
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