Uracil derivatives

Reaction of / fZ-amyl alcohol with urea in the presence of sulfuric acid gives a monoalkylated urea (61,62). Monoalkyl ureas are used to prepare uracil derivatives which are useful as herbicides, fungicides, and plant growth regulators (61). 

As mentioned above (Section 2.13.2.1.3), bipyrimidine photoproducts can arise, probably by reaction between two radicals. Thus, irradiation of an aqueous solution of 5-bromouracil (ill R=Br) in the absence of oxygen produces a variety of products including uracil, barbituric acid, 5-carboxyuracil (111 R = CO2H), several non-pyrimidine compounds and, as a stable end-product, the biuracil (114 R = H). A similar product (114 R = Me) is formed from 5-bromo-l,3-dimethyluracil (ilS). When two such related uracil derivatives are irradiated together, a mixed bipyrimidine product is formed, inter alia (B-76MI21302). 

Cytarabine, 4-amino-l-/3-D-arabinofuranosylpyrimidin-2(lif)-one or cytosine arabino-side (1033 R = H, X = NH2), is an established drug for the treatment of acute leukaemias of childhood and adult granulocytic leukaemia. It must be given intravenously and much of the drug becomes the corresponding inactive uracil derivative in vivo by virtue of a deaminase in the liver it interferes with DNA but not RNA synthesis, and it has incidental... 

Eosin Flavonoids Morin Flavonol, fisetin, robinetin Quercetin Rutin condensation products of urea, formaldehyde and methanol [126], pesticide derivatives [127] sweetening agents [128, 129] anion-active and nonionogenic surface-active agents [130] steroids, pesticides [29,132, 133] pesticides [134—137] vanadium in various oxidation states [138] uracil derivatives [139]... 

Malachite green (0.0...2.0) uracil derivatives, triazine herbicides [163] polar lipids [246, 247] phospholipids [248, 249] fatty acids, fatty aldehydes, phospholipids and glycolipids [250] microbiocidal isothiazolones [251]... 

Eurther quantum chemical studies involving uracil derivatives concern the conformations and properties of uridines [98CEJ621,98JA5488,98JOC1033, OOJCS (P2)677], the nucleophilic attack in pseudouridine synthases [99JA9928], and the aza analogs of uracil [99JST349]. 

This four-atom replacement was observed in some reactions of uracil derivatives, containing at position 5 a substituent with the CCCN moiety. Treatment of the Z-isomer 5-(2-carbamoylvinyl)-l,3-dialkyluracil with ethanolic sodium ethoxide gave in good yield 3-ethoxycarbonylpyridin-6(lf/)-one (84%) together with 3-A-methylcarbamoyl)pyridin-6-(l7 )-one (10%) (85JOC1513) (Scheme 26). The reaction involves an initial attack of the terminal amino group of the side-chain on position 6 of the uracil molecule. C-6-N-1 bond fission and N-C bond formation yield the pyridin-6(l//)-one. A subsequent attack of the ethoxide ion on the carbonyl groups of the side-chain yields both pyridin-2-one derivatives (Scheme 26). Similar results were obtained with the -isomer. 

Another ring-enlargement method for the formation of 1,3-diazocines employs the [2+2] photocycloadducts 3 of uracil derivatives and alkynes.4-5... 

Umbelliferone, pH-dependent change of fluorescence color 44 Universal reagents 4,46,195,376,402,405, 412, 430, 434 Uracil derivatives 44,45 Uranium cations 144 Uranyl acetate reagent 44 Urea... 

Basiuk, V. A. and Chuko, A. A., Selectivity of bonded stationary phases containing uracil derivatives for liquid chromatography of nucleic acid components, /. Chromatogr. Sci., 31, 120, 1993. 

Gustavsson T, Banyasz A, Lazzarotto E, Markovitsi D, Scalmani G, Frisch MJ, Barone V, Improta R (2006) Singlet excited-state behavior of uracil and thymine in aqueous solution a combined experimental and computational study of 11 uracil derivatives. J Am Chem Soc 128 607-619... 

Hydantoin, the cyclic form of hydantoic acid, was detected in the Murchison meteorite and also as a product of polymerisation of HCN (Ferris et al 1974). The yields obtained (based on cyanoacetaldehyde) were 18% for cytosine-N -acetic acid, but only 1.8% for the corresponding uracil derivative (1 mM cyanoacetaldehyde and 2 M hydantoic acid were allowed to react at around 373 K). 

Partly saturated pyrazino[l,2-r-]pyrimidines were prepared by formation of the pyrazine ring. 2-Substituted-8-hydroxy-3,4-dihydro-177,277-pyrazino[l,2-r-]pyrimidin-l-ones were prepared by a [6+0] synthesis involving cyclization of 6-hydroxy-pyrimidine-4-(fV-hydroxyethyl)carboxamides <2005W02005/087766>. The 2/7-pyra-zino[l,2-c]pyrimidine-3-carboxamide 164 (Y = NH) was formed from [5+1] atom fragments via the uracil derivative 163 (Y = NH) and DMF-dimethyl acetal. Compounds 163 were prepared from 6-chloromethyluracil and glycine methyl ester 162 (Y = NH) (Scheme 20) <2004W02004/014354>. 

Reaction of isofervenulin 268 (R = H) with ketones in the presence of diethylamine or excess of the latter gave pyrido[2,3-d]pyrimidinedione 299 (R1 = R2 = H) and uracil derivative 300 (89KGS274 90KGS1545). 

Uracil derivatives have also shown activity as NS5B inhibitors. Thus, the activity of 15, with an IC50 of 27 pM, is increased 7-fold for analog 16 (IC50 = 3.8 pM), though 16 is only slightly active in a cell-based replicon assay (EC50 = 32 pM). The free NH on the uracil core is required for activity [57]. 

Complementary triple hydrogen-bond formation involving transition metal complexes has been little studied. Mingos et al. [68] have investigated the cocrystallisation of platinum(II) complexes of the uracil derivative orotic acid (2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid), which generally coordinates as the dianion, and 2,6-diaminopyridine (2,6-dap), in which complementary A-D-A---D-A-D triple hydrogen bonds are formed between the orotate... 

The contents of the nucleic acid bases in the poly-L-lysine derivatives were determined by UV spectra of the polymers after hydrolysis The polymers were hydrolyzed in 6 N-hydrochloric acid at 105°C for 24 hr, into lysine dihydrochloride and the carboxyethyl derivatives of the nucleic acid bases. The quantitative calculation was made relative to the standard sample of the carboxyethyl derivative of the nucleic acid bases. The analytical data are listed in Table 1. It was found that the thymine and uracil derivatives was completely substituted to polylysine. Low value in case of adenine base in the polymer may be attributed to the unstability of the activated ester, Ade-PNP (2), and may also be explained in terms of the steric interaction among bulky pendant groups of the polymer. When the poly-L-lysine containing about 50 mol % adenine units was again treated with Ade-PNP, the adenine unit content in the polymer increased up to 74 mol %(,] ). 

Vollhardt and colleagues have explored the reactions between diynes and enami-nes338-341. The reactions between symmetrically substituted alkynes and alkyne tethered uracil derivatives proceeded in moderate yields, producing adducts with predominant anti configurations342-343. On the other hand, the reactions between diynes and uracil derivatives produced predominantly syn isomers. 

Caffeine pharmacokinetics are nonlinear. For example, when comparing a 500 mg dose to a 250 mg dose, the clearance is reduced and elimination half-life is prolonged with the higher dose (Kaplan et al. 1997). Thus, larger doses prolong the action of the drug. Active metabolites of caffeine are paraxanthine, and to a lesser degree, theobromine, and theophylline. Urinary metabolites are I-methylxanthine, l-methyluric acid, and an acetylated uracil derivative. 

Herbicidal and chemotherapeutic activity have also been noted in other dihydropyrimidines. Certain 5,5-dihalo-6-methoxydihydropyrimidines, especially the 3-substituted derivatives such as (LXXXIll), are reported to have herbicide activity against many grasses and broad-leaf weeds [645] (herbicidal activity of some corresponding A -substituted uracils has been discussed in the preceding section). The compounds can generally be prepared by halogenation of uracil derivatives in alcohol [646, 647]. 

Alkylation of pyridazinone 945 with 4-bromoacetoacelic acid 944 did not give the 2 -oxo-4 -carboxylic acid analogs, but gave 946 of type 4.1. The uracil derivatives were prepared similarly (90MI4). 

Alkylation of the uracil derivatives with the epoxide 1097 gave 1098, whose hydroxylation gave 1099, which had no significant activity against herpes simplex virus type 1 (94MI6). Uracil derivatives derived from 1068 were also prepared. 

Condensation with urea does not lead in this case, as would be expected, to the uracil derivative with ring closure, because the reaction takes place only at the more reactive aldehyde function ... 

Kyogoku Y, Lord RC, Rich A. An infrared study of hydrogen bonding between adenine and uracil derivatives in chloroform solution. J Am Chem Soc 1967a 89 496-504. 

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). 

The synthesis of 3-nitro-l-substituted uracil derivatives 30 can readily be performed with trifluoroacetic nitric anhydride, and this procedure is used in nucleoside chemistry to convert the uracil 3-nitrogen to a good leaving group <1995JA3665, 1997JOC1547, 20020L1827>. 

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