Uracil 5-fluorouracil

Among various pyrimidines tested in vitro as inhibitors of the active transport of uracil across the rat intestinal wall, strong inhibition was seen with 5-amino-uracil, 5-fluorouracil, 5-bromouracil and thymine [398]. 

The 5,6-double bond in uracil, 5-fluorouracil, /V-alkyluracils, thiouracils, and uridines adds sodium sulfite or bisulfite to give the corresponding 5,6-dihydro-6-sulfonic acid salts. Bisulfite addition to cytosines and cytidine may be succeeded by a second reaction involving nucleophilic replacement of the amino group, for example, by water. 

FIGURE 28. Energy-level diagram showing the four highest MOs in uracil, 5-fluorouracil, thymine, 5-(trifluoromethyl)uracil and l-methyl-5-(trifluoromethyl)uracil. Reproduced by permission of IUPAC from Reference 259... 

Condensation of 2-(benzyloxy)ethanol with a mixture of the hydrate and methyl hemiacetal of methyl glyoxalete 638 gave a hemiacetal, which was converted directly with methanesulfonyl chloride to a-chloro ether 639. It condensed with silylated uracil, 5-fluorouracil, and A -acetylcytosine,... 

When virus RNA is incubated with hydroxylamine at pH 6, cytosine reacts with hydroxylamine to yield a compound that codes like uracil. 5-Fluorouracil is incorporated into the virus RNA and replaces uracil in the sequence. In contrast to uracil, which can form hydrogen bonds with adenine only, 5-fluorouracil seems to be able to form hydrogen bonds with adenine or guanine. 

C4H4N2O2. Colourless crystalline powder, turning brown at 280 C and melting at 338 C (decomp.). Uracil is a constituent of ribose nucleic acid. Used as a diuretic and derivatives have pharmaceutical importance. 5-Fluorouracil is used in cancer treatment. 

Fluorinated Heterocyclic Compounds. HeterocycHc compounds containing the CF group are prepared by methods similar to those used in the fluorination of aHphatic compounds. The direct action of fluorine on uracil yields the cancer chemotherapy agent, 5-fluorouracil [51-21-8] as one special example of a selective fluorination on a commercial scale (25). 

Fluoropyrknidine derivatives are of tremendous importance in cancer chemotherapy, eg, 5-fluorouracil [51-21-8] (5-FU). The original 5-fluorouracil process featured a multistep low yield route based on ethyl fluoroacetate (451). Direct fluorination (fluorine) of uracil [66-22-8] gives high yields of 5-FU (452—455). This process has now been commercialized. 

Uracil is used more effectively, in nucleic acid synthesis within a rat hepatoma than in normal liver. This observation appears to have stimulated the synthesis of 5-fluorouracil (1027) as an antimetabolite mainly because the introduction of a fluorine atom involves a minimal increase in size. In the event, 5-fluorouracil did prove to have antineoplastic activity and it is now a valuable drug for treatment of tumors of the breast, colon or rectum, and to a lesser extent, gastric, hepatic, pancreatic, uterine, ovarian and bladder carcinomas. As with other drugs which interfere with DNA synthesis, the therapeutic index is quite low and great care is required during treatment (69MI21301). 

Lethal drug interactions of new antiviral, sorivudin [l-(3-D-arabinofuranosyl-( )-5-(2-bromvinyl)uracil], with anticancer prodrugs of 5-fluorouracil structure 97YZ910. 

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... 

Santoro F, Barone V, Gustavsson T, Improta R (2006) Solvent effect on the singlet excited-state lifetimes of nucleic acid bases a computational study of 5-fluorouracil and uracil in acetonitrile and water. J Am Chem Soc 128 16312-16322... 

Gamelin E, Boisdron-Celle M, Guer-in-Meyer V et al. Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer a potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage. J Clin Oncol 1999 17 1105-1110. 

The reaction of XeF2 with uracil produces the 5-fluoro derivative, which can be applied topically for treating some types of skin diseases including some types of skin cancer. The reaction producing 5-fluorouracil can be shown as... 

An interesting dinically useful prodrug is 5-fluorouracil, which is converted in vivo to 5-fluoro-2 -deoxyuridine 5 -monophosphate, a potent irreversible inactivator of thymidylate synthase It is sometimes charaderized as a dead end inactivator rather than a suicide substrate since no electrophile is unmasked during attempted catalytic turnover. Rathei since a fluorine atom replaces the proton found on the normal substrate enzyme-catalyzed deprotonation at the 5 -position of uracil cannot occur. The enzyme-inactivator covalent addud (analogous to the normal enzyme-substrate covalent intermediate) therefore cannot break down and has reached a dead end (R. R. Rando, Mechanism-Based Enzyme Inadivators , Pharm. Rev. 1984,36,111-142). 

Fluorouracil (5FU) is 5-fluoropyridrimidine-2,4(1/7, 3H)-dione. Its structure is illustrated in Figure 11. The hydrogen in the naturally occurring pyrimidine, uracil, is substituted by fluorine in the 5 position. The presence of the heteroatoms in the structure imparts hydrophilicity to the compound as they are capable of hydrogen bonding. 

The catalytic efficiency of this enzyme to hydrolyze 5-fluoro-5,6-dihydro-uracil was found to be approximately twice that toward 5,6-dihydrouracil [152], 2-Fluoro-/3-alanine can either be eliminated via the bile after conjugation with bile acids, or be converted to fluoroacetate (4.238) [153], The latter metabolite is transformed to fluorocitrate, a potent inhibitor of the aconi-tase-catalyzed conversion of citrate to isocitrate. This inhibition probably explains the clinical neurotoxicity of 5-fluorouracil [154] [155],... 

Although FdUrd produces only DNA-medicated cyotoxicity, 5-FU can also be metabolized to fluorouracil monophosphate (FUMP) and ultimately to fluorouracil triphosphate (FUTP), which can be incorporated into RNA in place of uridine triphosphate (UTP). In other words, incorporation of 5-FU into RNA mimics uracil de novo synthesis and affects the production of ribosomal RNAs (rRNAs) (16,17). 5 -FU also affects several aspects of messenger RNA (mRNA) function, including transcription (18), translation (19), and slicing (20). 

The pyrimidine antagonists inhibit the biosynthesis of pyrimidine nucleotides or interfere with vital cellular functions, such as the synthesis or function of nucleic acids. The analogues of deoxycytidine and thymidine that are used are inhibitors of DNA synthesis while 5-fluorouracil (5-FU) an analogue of uracil, is an inhibitor of both RNA function and of the synthesis of thymidylate (see Fig. 2). PALA (N-phosphonoacetyl-L-aspartate), an inhibitor of as-... 

The fluorine atom can be present in position 5 in uracil derivatives, or in position 1 in that of purine, as in fludarabine, which is used in the treatment of some leukemias (Figure 6.14 cf. Chapter 8). Nucleoside derivatives of fluorouracil (e.g., capecitabine) are prodrugs that allow the oral administration of 5-FU in cancer chemotherapy. The mechanism of action of these nucleosides is detailed in Chapters 7 and 8. Nucleosides having a trifluoromethylated base have been described for example, trifluridine is active on herpesvirus (Figure 6.14). 

Fluorouracil and its derivatives are still important dmgs in the chemotherapy of numerous cancers (doxifluridine, tegafur, carmofur) (cf. Chapter 8). Studies on the mechanism of action of 5-FU had great influence on the development of other antitumor drugs that are derived from pyrimidine and purine. 5-FU is industrially prepared by fluorination of uracil with elemental fluorine (cf. Figure 2.6, Chapter 2). 

Aromatic compounds can participate in both [2+2] and [4+2] photocycloaddition reactions with uracil derivatives to give either benzocyclobutane or ethenoquinazoline (barrelene) derivatives, which can then undergo a number of subsequent photochemical reactions. The products obtained are dependent upon the reaction conditions, and thus the photocycloaddition reaction between naphthalenes 470 and l,3-dimethyl-5-fluorouracil 471 in cyclohexane gave 4a-fluoro-5,10-ethenobenzo[/]quinazolines 472 as products as a result of a [4+2] photocycloaddition (photo-Diels-Alder) reaction <2002TL3113, 2003H(61)377>. 

Mechanism of Action An antifungal that penetrates fungal cells and is converted to fluorouracil which competes with uracil interfering with fungal RNA and protein synthesis. Therapeutic Effect Damages fungal membrane. 

The hydrate formed by photolysis of this substance is one of the few such products (the others are uracil hydrate, 5-fluorouracil hydrate, and uridine hydrate) that have actually been isolated and compared with authentic material of known structure.7 It is nearly the only product formed in the photolysis, is definitely stable at room temperature and neutral pH, and the thermal reversal to dimethyluracil is nearly quantitative. These properties, as Moore observed, make the reaction ideal for mechanistic investigation. Burr and Park have investigated the reaction mechanism by measuring the photolysis rate of dimethyluracil in mixtures of water with several nonaqueous, nonreactive solvents as a function of water concentration.64 The photolysis rate for 10" iM DMU was found to be the same in water-saturated cyclohexane (about 5 x 10-3M in water) as in dry cyclohexane. The photolysis rate in dry, highly purified dioxane was quite insensitive to water, and it was observed that hydrate formation (measured by thin-layer chromatography and by thermal absorbance reversal) became appreciable only at water concentrations above 40%. 

Up to 50% of the uracil residues in RNA can be replaced by 5-fluorouracil in various viruses and other biologically active nucleic acids. RNA containing fluorouracil is more sensitive to ultraviolet light than is normal RNA. The photochemical behavior of fluorouracil is therefore important, and has been studied by Shugar et al.67a and by Gordon. 7b... 

Thymidylate synthase (E.C. 2.1.1.45) is the enzyme that methylates UMP to thymidine, using methylene tetrahydrofolate as the carbon carrier. The enzyme can be inhibited directly by analogues of uracil such as 5-fluorouracil (8.34, 5-FU). The antimetabolite must be in the 5-fluorodeoxyuridine monophosphate (FdUMP) form to become active, and the capability of cells to achieve this transformation is a major determinant of their sensitivity to such drugs. 

Garg MB, Sevester JC, Sakoff JA et al. Simple liquid chromatographic method for the determination of uracil and dihydrouracil plasma levels a potential pretreatment predictor of 5-fluorouracil toxicity. J Chromatogr B Analyt Technol Biomed Life Sci 2002 774 223-230. 

Flucytosine is converted into the anti metabolite 5-fluorouracil that inhibits thymidilate synthetase, thereby disrupting DNA synthesis. It also interferes with protein synthesis by incorporation of fluorouracil into RNA in place of uracil. Although active against most Candida species, its spectrum of antifungal activity, overall, is narrow. Since resistance can develop rapidly it is usually coadministered with another agent and its main value is that it facilitates a reduction in the dose (and, presumably, the toxic effect) of amphotericin when co-prescribed in this way. The main adverse effects are marrow aplasia and hepatotoxicity. 

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. 

Fluorouracil has been used for some time for cancer treatment. Its preparation using fluorine is operated commercially (RC.R. Inc) and has been the focus of numerous studies [12, 150] in the past. In a more recent study, the products obtained upon fluorination of uracil, usually carried out in acetic acid solvent, indicate that the reactions proceed via an addition-elimination process involving radical cation intermediates (Fig. 63) [156]. 

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