Chemistry:Carmofur
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| Other names | 1-hexylcarbamoyl-5-fluorouracil, HCFU, N-hexylcarbamoyl-5-fluorouracil, Yamaful, NCGC00095165-01, Hexylcarbamoyl fluorouracil, 61422-45-5, UNII-HA82M3RAB2, CCRIS 2759, C11H16FN3O3, Uracil, 5-fluoro-1-hexylcarbamoyl-, BRN 0888898, HA82M3RAB2, 1(2H)-Pyrimidinecarboxamide, 5-fluoro-N-hexyl-3,4, |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration | Oral |
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| Formula | C11H16FN3O3 |
| Molar mass | 257.265 g·mol−1 |
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Carmofur (INN) or HCFU (1-hexylcarbamoyl-5-fluorouracil) is a pyrimidine analogue used as an antineoplastic agent. It is a derivative of fluorouracil, being a lipophilic-masked analog of 5-FU that can be administered orally.[1]
Biology
Carmofur prodrug is ingested and taken up in the intestine, overcoming the problem of 5-FU degradation by dihydropyrimidine dehydrogenase. Once inside a cell, the carmofur prodrug is converted into 5-FU.
Mechanism of action
The mechanism of action of carmofur prodrug is traditionally thought to be the generation of 5–FU.[2] However, carmofur is a highly potent acid ceramidase (AC) inhibitor.[2] Ceramide influences cancer cell survival, growth and death.[2] Inhibition of AC activity sensitizes tumor cells to the effects of antineoplastic agents and radiation.[2] Carmofur, much more effective than temozolomide, has been reported as the small-molecule drug capable of killing adult and pediatric glioblastomas.[3][4]
Medicinal uses
Product marketing for carmofur started in 1981. Carmofur has also been used as adjuvant chemotherapy for curatively resected colorectal cancer patients in China, Japan, and Finland for many years.[5] Trials and meta-analyses have confirmed that the drug is effective on patients with this cancer type, extending their survival.[6]
Carmofur has been shown to inhibit the SARS-CoV-2 main protease, and is therefore a promising lead compound to develop new antiviral treatment for COVID-19.[7]
Adverse effects
As fluorouracil, carmofur has been known to induce leukoencephalopathy, characterized by progressive damage to white matter in the brain with stroke-like symptoms.[8][9][10]
A clinical trial for small hepatocellular carcinoma was stopped prematurely because 56% of the treated patients had unacceptable side effects. Moreover, the treatment had no survival advantage for stage 1 and 2 cancer patients.[11] This may be a reason why carmofur was never pursued for FDA-approval in the US.[1]
Chemical synthesis
Ozaki et al. have reported a synthesis by treating 5-FU with phosgene and hexylamine.[12] Xiong et al. reported an alternative approach for the synthesis of carmofur . Chemical preparations and structures can be found here.[1]
References
- ↑ 1.0 1.1 1.2 "Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs". Chemical Reviews 116 (23): 14379–14455. December 2016. doi:10.1021/acs.chemrev.6b00209. PMID 27960273.
- ↑ 2.0 2.1 2.2 2.3 "Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity". Scientific Reports 3 (1035): 1035. Jan 2013. doi:10.1038/srep01035. PMID 23301156. Bibcode: 2013NatSR...3E1035R.
- ↑ "Acid ceramidase is a novel drug target for pediatric brain tumors". Oncotarget 8 (15): 24753–24761. April 2017. doi:10.18632/oncotarget.15800. PMID 28445970.
- ↑ "Acid ceramidase and its inhibitors: a de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency". Oncotarget 8 (68): 112662–112674. December 2017. doi:10.18632/oncotarget.22637. PMID 29348854.
- ↑ "Efficacy of oral anticancer agents for colorectal cancer". Diseases of the Colon and Rectum 49 (10 Suppl): S82–S91. October 2006. doi:10.1007/s10350-006-0601-7. PMID 17106820.
- ↑ "An individual patient data meta-analysis of adjuvant therapy with carmofur in patients with curatively resected colon cancer". Japanese Journal of Clinical Oncology 35 (9): 536–544. September 2005. doi:10.1093/jjco/hyi147. PMID 16155120.
- ↑ "Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur". Nature Structural & Molecular Biology 27 (6): 529–532. June 2020. doi:10.1038/s41594-020-0440-6. PMID 32382072.
- ↑ "Leukoencephalopathy following treatment with carmofur: a case report and review of the Japanese literature". Asia-Oceania Journal of Obstetrics and Gynaecology 15 (2): 161–168. June 1989. doi:10.1111/j.1447-0756.1989.tb00171.x. PMID 2667512.
- ↑ "[Leukoencephalopathy caused by antineoplastic drugs]" (in Japanese). Brain and Nerve = Shinkei Kenkyu No Shinpo 60 (2): 137–141. February 2008. PMID 18306661.
- ↑ "Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients". Journal of Neurology, Neurosurgery, and Psychiatry 79 (5): 535–539. May 2008. doi:10.1136/jnnp.2007.123737. PMID 17682013.
- ↑ "Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma". The British Journal of Surgery 83 (3): 336–340. March 1996. doi:10.1002/bjs.1800830313. PMID 8665186.
- ↑ "Synthesis and antitumor activity of 1- or 3-(alpha-hetero substituted)alkyl-5-fluorouracil derivatives". Nucleic Acids Symposium Series 18 (18): 1–4. 1987. PMID 3697106.
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