Trifluorothymidine

Trade Name Manufacturer Cou ntry Year Introduced 

A mixture of 17.2 grams of 2-trifluoromethylphenothiazine, 3.1 grams of sodamide and 14 grams of 1-(3 -chloropropyl)-4-methylpiperazine in 200 ml of xylene is heated at reflux for 2 hours. The salts are extracted into 150 ml of water. The xylene layer is then extracted with several portions of dilute hydrochloric acid. The acid extracts are combined and neutralized with ammonium hydroxide solution. The product, 10-[3 -(4 -methyl-1 piperazinyO-propyl]-2-trifluoromethylphenothiazine, is taken into benzene and purified by vacuum distillation, BP 202° to 210°C at 0.6 mm. 

Ullyot, G.E. U.S. Patent 2,921,069 January 12, I960 assigned to Smith Kline French Laboratories 

Chemical Name 2 -Deoxy-5-(trifluoromethyOuridine Common Name Trifluridine 

A suspension of 4.00 g (6.75 mmol) of 3, 5 - bis-0-(p-nitrobenzoyl)-2 -deoxy-5-(trifluoro-methyDuridine in 250 ml of methanol was treated with 10 ml of diisopropylamine and refluxed until it had dissolved (about IB minutes), and the solution was concentrated. The dry residue was partitioned between 50 ml of chloroform and 50 ml of water. The chloroform layer was washed with 20 ml of water, and the combined aqueous layers were concentrated. A low ultraviolet extinction ( 7200 and 262 m/U pH 1) and the presence of isopropyl signals in the NMR spectrum (two singlets at 78.73 and B.B5) indicated the dry residue contained diisopropylamine, probably as a salt with the relatively acidic heterocyclic N-H in 14. 

Therapeutic Function Antiviral (ophthalmic) Chemical Name 2 -Deoxy-5-(trifluoromethyl)uridine Common Name Trifluridine Structural Formula  

A solution in 75 ml of water was treated with 8 ml (volume of resin) of Dowex 50 (H), prewashed with water and methanol. The resin was removed on a filter and washed with 25 ml of methanol and 50 ml of water. The combined filtrate was evaporated in vacuo to form 1.99 g of 2 -deoxy-4-(trifluoromethyl)uridine (100%), melting point 171°C to 175°C. 

Heidelberger, C, U.S. Patent 3,201,387 August 17, 1965 assigned to the U.S. Secretary of Health, Education and Welfare 

Trade Name Manufacturer Country Year Introduced 

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A. El-Koussi, N. Bodor, Improved Delivery through Biological Membranes. XXV. Enhanced and Sustained Delivery of Trifluorothymidine to the Brain Using a Dihydropyridine <-> Pyridinium Salt Type Redox Delivery System , Drug Design Delivery 1987,... 

The metabolic fate of trifluridine (11.17), an antiviral agent closely related to 5-fluoro-2 -deoxyuridine, was comparable. The main metabolite in the urine of mice administered the drug was the free 5-trifluorothymidine, i. e., the product of C-N bond cleavage [39]. All other metabolites were products of further biotransformation of trifluorothymidine. 

Another relevant but poorly understood example is that of trifluridine (11.17), an important metabolite of which is the free 5-trifluorothymidine resulting from loss of the deoxyribosyl moiety (see Sect. 11.2.3). Of relevance here is the subsequent formation of 5-carboxyuracil (11.37) as a metabolite... 

A variety of mammalian cell culture systems can be used to detect mutations induced by chemical substances. The L5178Y mouse l)nnphoma line, measuring mutation at the TK locus, is preferred. TK is an important enz)une involved in DNA synthesis. Cells are exposed to the test substance at various concentrations, in the presence and absence of a metabolic activation system, for a suitable period of time, and then subcultured to assess cytotoxicity and to allow phenotypic expression prior to mutant selection. Cells deficient in TK because of a forward mutation are resistant to the cytotoxic effects of pyrimidine analogues (antimetabolites), such as trifluorothymidine (TFT). This is because the antimetabolites cannot be incorporated into cellular nucleotides and kill the cell through inhibition of cellular metabolism. After treatment, cells are grown in a medium containing TFT mutant cells can proliferate in the presence of TFT, whereas normal cells containing TK are killed. This allows the detection of an increase in mutant... 

Amacher DE, Paillet SC. 1980. Induction of trifluorothymidine resistant mutants by metal ions in E5178Y/TK+/- cells. Mutat Res 78 279-288. 

Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses. It is phosphorylated intracellularly by host cell enzymes, and then competes with thymidine triphosphate for incorporation by the viral DNA polymerase (Figure 49-3). Incorporation of trifluridine triphosphate into both viral and host DNA prevents its systemic use. Application of a 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous application of trifluridine solution, alone or in combination with interferon alfo, has been used successfully in the treatment of acyclovir-resistant HSV infections. 

Cliromosome analysis of trifluorothymidine-resistant L5178Y mouse lymphoma cell... 

Thiopentone (thiopental) Trifluorothymidine (trifluridine) Troxidone (trimethadione)... 

Research in antiviral chemotherapy began in the early 1950s, when the search for anticancer drugs generated several new compounds capable of inhibiting viral DNA synthesis. The two first-generation antivirals, 5-iododeoxyuridine and trifluorothymidine, had poor specificity (ie, they inhibited host cellular as well as viral DNA) that rendered them too toxic for systemic use. However, both are effective when used topically for the treatment of herpes keratitis. 

THYMIDINE KINASE (TK) An enzyme involved in the utilization of the nucleoside thymidine (which ultimately becomes part of the structure of DNA) catalyzes the phosphorylation of thymidine to thymidine monophosphate mutants that lack TK are resistant to the toxic effects of several thymidine analogues, including bromodeoxy-uridine and trifluorothymidine selection of these drug-resistant mutants provides the basis of several... 

Mutation assay Positive controls (HYC and DMBA) and five concentrations of the test article used with and with metabolic activation Cells exposed to each dose, and the supernatant obtained, and incubated for 20 and 44 hours After a 2-day expression period, the cultures cloned with the restrictive agent trifluorothymidine (allows the growth of TK-/- cells only) or vehicle control... 

Point mutation tests have been developed also for cultured mammalian cells (de Marini et al, 1989). These tests are based on the mutational resistance to otherwise cytotoxic agents (i.e. TKor HPRT mutations, conferring resistance to trifluorothymidine and 6-thioguanine, respectively). Compared to the Ames test and other bacterial assays they are, however, more laborious and time consuming. 

C10H11F3N2O5 trifluorothymidine 70-00-8 25.00 1.4365 2 19440 C10H12N2O 1-phenyl-4-methyl-3-pyrazolidone 2654-57-1 25.00 1.1112 2... 

Cirkel PK, van Ketel WG. Allergic contact dermatitis to trifluorothymidine eyedrops. Contact Dermatitis 1981 7(l) 49-50. 

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