Pyrimidines, fluorinated

Fluorouracil (5-fluorouracil, 5-FU, Fig. 5) represents an early example of rational drag design in that it originated from the observation that tumor cells, especially from gut, incorporate radiolabeled uracil more efficiently into DNA than normal cells. 5-FU is a fluorinated pyrimidine analog that must be activated metabolically. In the cells 5-FU is converted to 5-fluoro-2>deoxyuridine-monophosphate (FdUMP). This metabolite inhibits thymidilate synthase which catalyses the conversion of uridylate (dUMP) to thymidilate (dTMP) whereby methylenetetrahydrofo-late plays the role of the carbon-donating cofactor. The reduced folate cofactor occupies an allosteric site of... 

Heidelberger C (1965) Fluorinated pyrimidines. In Davidson JN, Cohn WE (eds) Progress in nucleic acid research and molecular biology, vol 4. Academic Press, New York, p 1... 

Pharmacology A fluorinated pyrimidine nucleoside with in vitro and in vivo activity against herpes simplex virus types 1 and 2, and vaccinia virus. Some strains of adenovirus are also inhibited in vitro. Its antiviral mechanism of action is not completely known. 

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. 

C. Heidelberger, Fluorinated pyrimidines, a new class of tumour-inhibitory compounds, Nat. Chem. Biol. 179 (1957) 663-666. 

C. Heidelberger, N.K. Chaudhuri, P. Danenberg, D. Mooren, L. Griesbach, R. Duschinsky, J. Schnitzer, E. Pleven, J. Scheiner, Fluorinated pyrimidines A new class of tumour-inhibitory compounds. Nature 179 (1957) 663-666. 

Fluorinated pyrimidines hydrolyze more readily than the other halogen derivatives and thus 5-trifluoromethyluracil 169 was able to be obtained from 2,6-difluoro-5-trifluoromethylpyrimidine 168 simply by heating with potassium fluoride in water at 50 °C <1996JFC(77)93>. 

It is a synthetic fluorinated pyrimidine anti-metabolite which acts by its conversion to anti-metabolite 5-fluorouracil which inhibit DNA s5mthesis. 

Fluorouracil, a fluorinated pyrimidine antimetabolite is used topically for the treatment of multiple actinic keratoses and intralesionally for keratoacanthomas. 

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. 

Fluorouracil is a fluorinated pyrimidine antimetabolite that resembles uracil, with a fluorine atom substituted for the 5-methyl group. Its systemic pharmacology is described in Chapter 54. Fluorouracil is used topically for the treatment of multiple actinic keratoses. 

Trifluoromethylation is the most important perfluoroalkylation reaction. Kobayashi and co-workers reported the trifluoromethylation of aryl, vinyl, alkyl halides with trifluoromethyl iodide in the presence of copper powder in aprotic solvents such as HMPA at 120-150 °C [83,84], and this methodology has been applied to the preparation of fluorinated pyrimidine and purine nucleosides [85,86] (Scheme 27). 

Halogen exchange reactions, too, are valuable sources of fluorinated pyrimidines, especially 2-, 4-, and 6-fluoro derivatives. Sources of fluoride ion have included hydrogen, sodium, potassium, cesium, antimony, silver fluorides, and sulfur tetrafluoride. All of the reactions required heating. Prepared from nucleophilic fluorination processes have been... 

Sullivan RD, Y oung CW, Miller E, Glatstein N, Qarkson B, Burchenal JH. The chnical effects of the continnous administration of fluorinated pyrimidines (5-flnoronracil and 5-fluoro-2 -deoxyuridine). Cancer Chemother Rep 1960 8 77-83. 

Moertel CG, Reitemeier RJ, Bolton CF, Shorter RG. Cerebellar ataxia associated with fluorinated pyrimidine therapy. Cancer Chemother Rep 1964 41 15-18. 

Grem JL. Fluorinated pyrimidines. In Chabner BA, Collins JM, editors. Cancer Chemotherapy Principles and Practice. Philadelphia Lippincoft, 1990 180-225. 

Flucytosine is a fluorinated pyrimidine that is transported across the fungal cell wall by a permease, where it is deaminated to the cytotoxic principal fluorouracil. Some fungi may lack the permease and are resistant to the drug and its clinical use is usually restricted to treating Candida spp. infection, although even here resistance may arise. It is synergistic with amphotericin B and... 

The limited therapeutic activity of the fluorinated pyrimidines 5-fluorouracil (FU) and 5-fluoro-2 -deoxyuridine (FUdR) in certain forms of adenocarcinoma, principally of the digestive tract, have led to the synthesis of a variety of analogues. Dinucleoside phosphates containing FU... 

Since p 5-fluoro-2-deoxyuridylyl-(5 -5 )-p-5-fluorodeoxyuridine did not inhibit growth of Ehrlich ascites tumor cells resistant to FUdR, 7 the aforementioned hope has not been realized. A series of 5-halo-6-oxydi-hydro derivatives of the fluorinated pyrimidines has proven resistant to... 

Flucytosine (also known as 5-flucytosine or 5-FC) is a fluorinated pyrimidine analogue that is highly water-soluble. Patients with creatinine clearances of less than 40 mL/min should receive 100-150 mg/kg daily in four divided doses. The dosage should be reduced by 50% in patients with a creatinine clearance of 25-50 mL/min and by 75% in patients with a clearance of 13-25 mL/min. Peak serum concentrations (2 hours after an oral dose) should be monitored in aU patients (particularly those with a creatinine clearance of less than 10 mL/min) to maintain peak serum concentrations of more than 100 mg/L.2 -29... 

Investigational Approaches. Despite the significant reduction in cancer recurrence and increased survival afforded with fluorouracil-based adjuvant chemotherapy, the results obtained thus far indicate need for continued improvement. Several strategies are underway, including protracted fluorouracil infusion, oral fluorinated pyrimidines, irinotecan, oxaliplatin, and immunotherapy-based therapies. ... 

Leichman CG. Prolonged infusion of fluorinated pyrimidines in gastrointestinal malignancies A review of recent clinical trials. Cancer Invest 1994 12 166-175. 

Fluoro and 2,4-difluoropyrimidines have also been prepared in good yields directly from pyrimidinones by the use of anhydrous potassium fluoride in tetraglyme-18-crown-6 at elevated temperature <85JHC145>. Synthesis of fluorinated pyrimidines via diazonium salts appears to be inferior to other methods <85JHC145>. 

Flucytosine is a fluorinated pyrimidine related to fluorou-racil and floxuridine. It is a 5-fluorocytosine. Flucytosine has clinically useful activity against Cryptococcus neofor-mans, Candida spp., and the agents of chlomoblastomycosis. Within these species, determination of susceptibility in vitro has been extremely dependent on the method employed, and susceptibility testing perfonned on isolates obtained prior to treatment has not correlated with clinical outcome. 

Flucytosine is an antimetabolite whose spectrum of antigungal activity is considerably more restricted than that of amphotericin B. Flucytosine is a fluorinated pyrimidine ... 

Trifluridine (5-trifluoromethyl-2 -deoxyuridine) is a fluorinated pyrimidine nucleoside with in vitro inhibitory activity against HSV types 1 and 2, CMV, vaccinia, and some adenoviruses. 

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