70-00-8

Indications

Trifluridine (Viroptic) is a fluorinated pyrimidine nucleoside that has in vitro activity against HSV-1 and HSV- 2, vaccinia, and to a lesser extent, some adenoviruses. Activation of trifluridine requires its conversion to the 5 monophosphate form by cellular enzymes.Trifluridine monophosphate inhibits the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) by thymidylate synthetase. In addition, it competes with deoxythymidine triphosphate (dTTP) for incorporation by both viral and cellular DNA polymerases. Trifluridine-resistant mutants have been found to have alterations in thymidylate synthetase specificity.

Biochem/physiol Actions

Trifluorothymidine is a thymidine analog and is light sensitive. TFT serves as a thymidine kinase substrate to study enzyme specificity and kinetics. Incorporation of phosphorylated TFT into DNA induces damage, making it useful for DNA repair studies. TFT may also be used in the inhibition of thymidylate synthase and in screening mutant thymidine kinase gene.. It elicits antitumor activity in gastrointestinal (GI) cancers and has therapeutic potential to treat herpetic keratitis.

Mechanism of action

Trifluorothymidine is a fluorinated pyridine nucleoside structurally related to idoxuridine. It has been approved by the U.S. FDA and is a potent, specific inhibitor of replication of HSV-1 in vitro. Its mechanism of action is similar to that of idoxuridine. Like other antiherpes drugs, it is first phos-phorylated by thymidine kinase to mono-, di-, and triphosphate forms, which are then incorporated into viral DNA in place of thymidine to stop the formation of late virus mRNA and subsequent synthesis of the virion proteins.

Pharmacokinetics

Trifluorothymidine is a synthetic halogenated pyrimidine nucleoside, first synthesized as an antitumor agent. It inhibits enzymes of the DNA pathway and is incorporated into both cellular and progeny viral DNA, causing faulty transcription of late messenger RNA and the production of incompetent virion protein. It does not require a viral thymidine kinase for monophosphorylation and is far less selective and more toxic than other analogs. It is active against HSV-1 and HSV-2, vaccinia virus, CMV and possibly adenovirus. Trifluorothymidine, when given IV, shows a plasma half-life of 18 minutes and is excreted in the urine either unchanged or as the inactive metabolite 5-carboxyuracil. When applied as a 1% ophthalmic solution, it rapidly enters the aqueous humor of HSV-infected rabbits’ eyes but is cleared within 60–90 min.

Side effects

The most frequent adverse reactions to trifluridine administration are transient burning or stinging and palpebral edema. Other adverse reactions include superficial punctate keratopathy, epithelial keratopathy, hypersensitivity, stromal edema, irritation, keratitis sicca, hyperemia, and increased intraocular pressure. Trifluridine is mutagenic in vitro and carcinogenic and teratogenic when administered subcutaneously to animals. Topical trifluridine was not teratogenic in animal studies. Because it is applied topically in humans, the likelihood of systemic effects is low.

Synthesis

Trifluridine, 5-trifluoromethyl-1-(2-deoxyribofuranosyl)pyrimidin-2, 4-(1H.3H)-dione (36.1.22), is synthesized from 5-trifluoromethyluracil. This is synthesized by the following scheme. It begins with trifluoroacetone, from which the oxynitrile (36.1.16) is synthesized. Acetylation of this product gives the corresponding trifluoroacetate (36.1.16). Pyrrolysis of Trifluridine gives trifluoromethylacrylonitrile (36.1.17). Adding to this dry hydrogen bromide in methanol solution in a process of which methanolysis of the nitrile group takes place the bromide 36.1.19 is obtained, which upon acidic hydrolysis undergoes heterocyclization to the dihydropyrimidine 36.1.20. Brominating of the obtained dihydropyrimidine with molecular bromine and subsequent dehydrobromination of the resulting product 36.1.21 on heating in dimethylformamide gives 5-trifluoromethyluracil (36.1.22). This is reacted with 2-deoxy-D-ribos-1-phosphate using the nucleoside phosphorylase enzyme, or by treating it with hyxamethyldisylazane and then with trichloromethylsilane to make 2,4- trimethylsilyloxy-5-trifluoromethyl pyrimidine (36.1.23). Hexamethyldisilazane, which itself does not form trimethylsilyl ethers, is used because using a combination of two reagents leads to optimal yield of trimethylsilyl ethers. Reacting the resulting pyrimidine derivative with 3,5-bis-(4-nitrobenzoate)-2-deoxyribofuranosyl chloride in the presence of mercury (II) acetate makes the corresponding ditrimethylsilyloxy nucleoside, which when treated with an aqueous solution of potassium iodide to remove the protecting groups. The resulting product undergoes preliminary purification by chromatography, and then is treated with a methanol solution of diisopropylamine to remove the 4-nitrobenzoyl protection from the furanosyl part, giving the desired trifluridine.

Veterinary Drugs and Treatments

Trifluridine (trifluorothymidine; Viroptic?) is a pyrimidine nucleoside analog. It is structurally related to 2-deoxythymidine, the natural precursor of DNA synthesis. Trifluridine is poorly absorbed by the cornea and is virostatic. Viroptic? interrupts viral replication by substituting “nonsense” pyrimidine analogues. For this reason, a competent surface immunity is necessary to resolve ocular disease, with or without antiviral therapy. A recent in vitro study in which several strains of feline herpes virus were collected from the United States and were used to infect kidney epithelial cells showed that trifluridine was more effective at lower concentrations compared with several other agents. For this reason, trifluridine was the first choice drug employed in the treatment of feline herpes virus ocular disease for many years. Because of the topical toxicity associated with use of trifluridine in cats, its popularity has diminished greatly. In many milder cases, the irritation associated with topical trifluridine is more intense then the inflammation induced by viral infection. Antiviral agents have also been used in the treatment of superficial punctate keratitis in the horse, thought to be associated with equine herpes virus-2 (EHV-2) infection of the cornea.

General Description

Trifluridine (F3Thd) is a nucleoside analogue with notable antitumor properties, though its efficacy is limited by rapid degradation in plasma. To improve its stability and activity, various acyl derivatives were synthesized, with the 5'-O-hexanoyl compound demonstrating the highest antitumor potency, significantly outperforming the parent compound. These modifications, particularly at the 5'-O position, enhance resistance to enzymatic degradation, thereby maintaining higher plasma concentrations and improving therapeutic outcomes. However, excessive protection of the sugar moiety or N3-acylation reduces activity, indicating the importance of selective derivatization for optimal efficacy.

Definition

ChEBI: Trifluridine is a pyrimidine 2'-deoxyribonucleoside compound having 5-trifluoromethyluracil as the nucleobase. An antiviral drug used mainly in the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis. It has a role as an antiviral drug, an antimetabolite, an EC 2.1.1.45 (thymidylate synthase) inhibitor and an antineoplastic agent. It is a nucleoside analogue, an organofluorine compound and a pyrimidine 2'-deoxyribonucleoside.

Brand name

Viroptic (Monarch).