Carmofur Explained

Verifiedfields:changed
Verifiedrevid:388677486
Iupac Name:5-fluoro-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide
Routes Of Administration:Oral
Cas Number:61422-45-5
Atc Prefix:L01
Atc Suffix:BC04
Pubchem:2577
Chembl:460499
Drugbank:DB09010
Unii:HA82M3RAB2
Chemspiderid:2479
Stdinchi:1S/C11H16FN3O3/c1-2-3-4-5-6-13-10(17)15-7-8(12)9(16)14-11(15)18/h7H,2-6H2,1H3,(H,13,17)(H,14,16,18)
Stdinchikey:AOCCBINRVIKJHY-UHFFFAOYSA-N
C:11
H:16
F:1
N:3
O:3
Smiles:CCCCCCNC(=O)N1C=C(C(=O)NC1=O)F
Synonyms: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,

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. However, carmofur is a highly potent acid ceramidase (AC) inhibitor. Ceramide influences cancer cell survival, growth and death. 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]

Notes and References

  1. Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF . Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs . Chemical Reviews . 116 . 23 . 14379–14455 . December 2016 . 27960273 . 7717319 . 10.1021/acs.chemrev.6b00209 .
  2. Realini N, Solorzano C, Pagliuca C, Pizzirani D, Armirotti A, Luciani R, Costi MP, Bandiera T, Piomelli D . 6 . Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity . Scientific Reports . 3 . 1035 . 1035 . Jan 2013 . 23301156 . 3539145 . 10.1038/srep01035 . 2013NatSR...3E1035R .
  3. Doan NB, Nguyen HS, Montoure A, Al-Gizawiy MM, Mueller WM, Kurpad S, Rand SD, Connelly JM, Chitambar CR, Schmainda KM, Mirza SP . 6 . Acid ceramidase is a novel drug target for pediatric brain tumors . Oncotarget . 8 . 15 . 24753–24761 . April 2017 . 28445970 . 5421885 . 10.18632/oncotarget.15800 .
  4. Doan NB, Alhajala H, Al-Gizawiy MM, Mueller WM, Rand SD, Connelly JM, Cochran EJ, Chitambar CR, Clark P, Kuo J, Schmainda KM, Mirza SP . 6 . 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 . 29348854 . 5762539 . 10.18632/oncotarget.22637 .
  5. Sakamoto J, Oba K, Matsui T, Kobayashi M . Efficacy of oral anticancer agents for colorectal cancer . Diseases of the Colon and Rectum . 49 . 10 Suppl . S82–S91 . October 2006 . 17106820 . 10.1007/s10350-006-0601-7 . 30655861 .
  6. Sakamoto J, Hamada C, Rahman M, Kodaira S, Ito K, Nakazato H, Ohashi Y, Yasutomi M . 6 . 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 . 16155120 . 10.1093/jjco/hyi147 . free .
  7. Jin Z, Zhao Y, Sun Y, Zhang B, Wang H, Wu Y, Zhu Y, Zhu C, Hu T, Du X, Duan Y, Yu J, Yang X, Yang X, Yang K, Liu X, Guddat LW, Xiao G, Zhang L, Yang H, Rao Z . 6 . 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 . 32382072 . 10.1038/s41594-020-0440-6 . free .
  8. Yamada T, Okamura S, Okazaki T, Ushiroyama T, Yanagawa Y, Ueki M, Sugimoto O, Yamazaki H, Sugino M, Masui Y . 6 . 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 . 2667512 . 10.1111/j.1447-0756.1989.tb00171.x .
  9. Mizutani T . [Leukoencephalopathy caused by antineoplastic drugs] . Japanese . Brain and Nerve = Shinkei Kenkyu No Shinpo . 60 . 2 . 137–141 . February 2008 . 18306661 .
  10. Baehring JM, Fulbright RK . Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients . Journal of Neurology, Neurosurgery, and Psychiatry . 79 . 5 . 535–539 . May 2008 . 17682013 . 10.1136/jnnp.2007.123737 . 38293604 .
  11. Yamamoto M, Arii S, Sugahara K, Tobe T . Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma . The British Journal of Surgery . 83 . 3 . 336–340 . March 1996 . 8665186 . 10.1002/bjs.1800830313 . 28134419 . free .
  12. Ozaki S, Nagase T, Ahmad S, Tamai H, Hoshi A, Iigo M . Synthesis and antitumor activity of 1- or 3-(alpha-hetero substituted)alkyl-5-fluorouracil derivatives . Nucleic Acids Symposium Series . 18 . 18 . 1–4 . 1987 . 3697106 .

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