Carmofur (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

) or HCFU (1-hexylcarbamoyl-5-fluorouracil) is a

pyrimidine analogue Pyrimidine analogues are antimetabolites which mimic the structure of metabolic pyrimidines. Examples * Nucleobase analogues **Fluorouracil (5FU), which inhibits thymidylate synthase **Floxuridine (FUDR) ** 6-azauracil (6-AU) *Nucleoside analogues ...

used as an antineoplastic agent. It is a derivative of

fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pa ...

, being a lypophilic-masked analog of 5-FU that can be administered orally.

Biology

Carmofur prodrug is ingested and taken up in the intestine, overcoming the problem of 5-FU degradation by

dihydropyrimidine dehydrogenase In enzymology, a dihydropyrimidine dehydrogenase (NADP+) () is an enzyme that catalyzes the chemical reaction :5,6-dihydrouracil + NADP+ \rightleftharpoons uracil + NADPH + H+ Thus, the two substrates of this enzyme are 5,6-dihydrouracil and ...

. Once inside a cell, 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 The ASAH1 gene encodes in humans the ''acid ceramidase'' enzyme. Function This gene encodes a heterodimeric protein consisting of a nonglycosylated alpha subunit and a glycosylated beta subunit that is cleaved to the mature enzyme posttr ...

(AC) inhibitor.

Ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetyl sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane The cell membrane (also known as the plasma membrane (PM) o ...

influences cancer cell survival, growth and death. Inhibition of AC activity sensitizes tumor cells to the effects of antineoplastic agents and radiation. Carmofur, much more effective than

temozolomide Temozolomide (TMZ), sold under the brand name Temodar among others, is a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. Text was copied from this source which is © European Medicines Agency. Reproduction ...

, has been reported as the small-molecule drug capable of killing adult and pediatric

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality cha ...

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. Trials and

meta-analyses A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...

have confirmed that the drug is effective on patients with this cancer type, extending their survival. 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 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quickl ...

Adverse effects

As fluorouracil, carmofur has been known to induce

leukoencephalopathy Leukoencephalopathy (leukodystrophy-like diseases) is a term that describes all of the brain white matter diseases, whether their molecular cause is known or unknown. It can refer specifically to any of these diseases: *Progressive multifocal leuko ...

, characterized by progressive damage to white matter in the brain with stroke-like symptoms. 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. This may be a reason why carmofur was never pursued for FDA-approval in the US.

Chemical synthesis

Ozaki et al. has reported carmofur synthesized by treating 5-FU with phosgene and hexylamine. Xiong et al. reported an alternative approach for carmofur synthesis. Chemical preparations and structures can be found here.

References

{{Chemotherapeutic agents Pyrimidinediones Organofluorides Pyrimidine antagonists Fluoropyrimidines SARS-CoV-2 main protease inhibitors