Fluorouracil, structure

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

Therapeutic Function Cancer chemotherapy Chemical Name 5-fluoro-2,4(1 H,3H)-pyrimidinedione Common Name 5-fluorouracil Structural Formula h... 

The following biochemically related F-NMR studies ot structure or tunebon have been published nucleic acid components (mainly 5-fluorouracil) [86... 

The antimetabolites interfere with various metabolic functions of cells, thereby disrupting normal cell functions. They inactivate enzymes or alter the structure of DNA, changing the DNA s ability to replicate These drag are most effective in the treatment of rapidly dividing neoplastic cells. Examples of the antimetabolites include methotrexate and fluorouracil (Adrucil). 

Chemical structure of monomers and intermediates was confirmed by FT-IR and FT-NMR. Molecular weight distribution of polymers was assessed by GPC and intrinsic viscosity. The thermal property was examined by differential scanning calorimetry. The hydrolytic stability of the polymers was studied under in vitro conditions. With controlled drug delivery as one of the biomedical applications in mind, release studies of 5-fluorouracil and methotrexate from two of these polymers were also conducted. 

Since many essential nutrients (e.g., monosaccharides, amino acids, and vitamins) are water-soluble, they have low oil/water partition coefficients, which would suggest poor absorption from the GIT. However, to ensure adequate uptake of these materials from food, the intestine has developed specialized absorption mechanisms that depend on membrane participation and require the compound to have a specific chemical structure. Since these processes are discussed in Chapter 4, we will not dwell on them here. This carrier transport mechanism is illustrated in Fig. 9C. Absorption by a specialized carrier mechanism (from the rat intestine) has been shown to exist for several agents used in cancer chemotherapy (5-fluorouracil and 5-bromouracil) [37,38], which may be considered false nutrients in that their chemical structures are very similar to essential nutrients for which the intestine has a specialized transport mechanism. It would be instructive to examine some studies concerned with riboflavin and ascorbic acid absorption in humans, as these illustrate how one may treat urine data to explore the mechanism of absorption. If a compound is... 

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. 

Fig. 2. Structure of fluorouracil (5-FU) and floxuridine (5-fluoro-2 -deoxyuridine, FdUrd).

The exceptional case where no activating group is required is the use of diaryliodonium salts as precursors for labelling, permitting the fluorine-18-labelling of relatively electron-rich structures [192-194], A recent example of successful application is the preparation of 5-[ F]fluorouracil in 40% radiochemical yield (Scheme 44) [202], However, this methodology appears to be relatively difficult to use with complex structures [203-205],... 

C. Punt, A. van der Kogel, A. Heerschap, Carbogen breathing differentially enhances blood plasma volume and 5-fluorouracil uptake in two murine colon tumor models with distinct vascular structures. Proc. Inti. Soc. Mag. Reson. Med. (Seattle) 2006, p. 1766. 

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%. 

However, in many cases the structure of the drug does not match the structure of the reactive groups on the polymeric carrier. In this case, the structure of at least one reactant has to be modified before conjugation. Derivatives of 5-fluorouracil, namely l-(3-bromopropionyl)-5-fluorouracil, 1-chlorocarbonyl-5-fluorouracil, and l-(4-bromobutyl)-5-fluorouracil were synthesized to permit the drug attachment to poly(L-cysteine) [146] (Fig. 6). 

A number of drug molecules contain a modified pyrimidine skeleton, the best known examples being the anticancer drug 5-fluorouracil, which is structurally similar to thymine, the antiviral drug AZT, currently being used in the treatment of AIDS, and phenobarbital, a well known sedative. 

As active transport uses a carrier system, it is normally specific for a particular substance or group of substances. Thus, the chemical structure of the compound and possibly even the spatial orientation are important. This type of transport is normally reserved for endogenous molecules such as amino acids, required nutrients, precursors, or analogues. For example, the anticancer drug 5-fluorouracil (Fig. 3.6), an analogue of uracil, is carried by the pyrimidine transport system. The toxic metal lead is actively absorbed from the gut via the calcium transport system. Active uptake of the toxic herbicide paraquat into the lung is a crucial part of its toxicity to that organ (see chap. 7). Polar and nonionized molecules as well as lipophilic molecules may be transported. As active transport may be saturated, it is a zero-order rate process in contrast to passive diffusion (Fig. 3.3). 

The broad peaks B, D, and E are shifted far upfield by reaction with bisulfite (Eq. 5-11) suggesting that they are not hydrogen bonded and are present in the loop of the stem-loop structure. Peaks A, E, F, and G correspond to resonances 64, 7, 67, and 4, respectively, in (A) and represent fluorouracil in the stem structure. From Chu et al.69i Courtesy of Jack Horowitz. (C) A 31P NMR spectrum of a synthetic 14 base-pair DNA segment related to the E. coli lac operator. The palindromic sequence is TCTGAGCGCTCAGA. The numbers refer to the positions from the 5 end. From Schroeder et al.688... 

Because 5-fluorouracil acts on normal cells as well as cancer cells, its usefulness is limited. Knowledge of the chemistry and three-dimensional structure of thymidylate synthase complexes is being used in an attempt to discover more specific and effective drugs that attack this enzyme.g/h... 

Fluorouracil is one component of a mixture of three drugs used in breast-cancer chemotherapy. What is its structure ... 

The photoaddition of water to a variety of naturally occurring pyrimidine derivatives has been reported. Photolysis in aqueous solution of uracil (224 R = H), uridine (224 R=ribosyl), and uridylic acid results in the formation of the corresponding 6-hydroxy-5,6-dihydropyrimidine (225)208-210 these structures have been established by independent synthesis.209 Analogous photoadditions have been observed in 1,3-dimethyluracil211 and 5-fluorouracil.212 These additions are reversible. 

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