Semustine

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]

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.

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]

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]

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.

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]

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]