Uracil, amino 5-hydroxy

Schiedt J, Weinkauf R, Neumark DN, Schlag E (1998). Anion spectroscopy of uracil, thymine and the amino-oxo and amino-hydroxy tautomers of cytosine and their water clusters. Chem Phys 239 511-524. 

Figure 4 Separation of chromatographic test mix showing generic method diversity. Separation conditions are identical to those reported in Figure 2B. Peaks 1 -5 are uracil, l-hydroxy-7-azabenzotriazole, methoxybenzenesulfonamide, methyl-3-amino-2-thio-phenecarboxylate, and 4-aminobenzophenone, respectively.

Direct bromination readily yields the 6-bromo derivative (111), just as with uracil. Analogous chlorination and iodination requires the presence of alkalies and even then proceeds in low yield. The 6-chloro derivative (113) was also obtained by partial hydrolysis of the postulated 3,5,6-trichloro-l,2,4-triazine (e.g.. Section II,B,6). The 6-bromo derivative (5-bromo-6-azauracil) served as the starting substance for several other derivatives. It was converted to the amino derivative (114) by ammonium acetate which, by means of sodium nitrite in hydrochloric acid, yielded a mixture of 6-chloro and 6-hydroxy derivatives. A modified Schiemann reaction was not suitable for preparing the 6-fluoro derivative. The 6-hydroxy derivative (115) (an isomer of cyanuric acid and the most acidic substance of this group, pKa — 2.95) was more conveniently prepared by alkaline hydrolysis of the 6-amino derivative. Further the bromo derivative was reacted with ethanolamine to prepare the 6-(2-hydroxyethyl) derivative however, this could not be converted to the corresponding 2-chloroethyl derivative. Similarly, the dimethylamino, morpholino, and hydrazino derivatives were prepared from the 6-bromo com-pound. ... 

Preparation of 5-[bis/2-Hydroxyethyl)Amino] Uraci/ 20 grams (0.157 mol) of 5-amlno-uracil was mixed with 350 ml of water, 23 ml of glacial acetic acid, and 160 ml of ethylene oxide in a one-liter flask immersed in an ice bath. The reaction mixture was stirred and allowed to come to room temperature slowly (as the ice melted), and stirring was continued for two days. A clear solution resulted to which was added 250 ml of water and 60 grams of Dowex-50 in the acid form. The mixture was stirred for 15 minutes, and the resin was collected on a filter. It was washed with water and the crude 5-[bis(2.hydroxy-ethyl)amino] uracil was eluted with a 10% aqueous solution of ammonium hydroxide. 

Undissolved substances were removed by filtration and the filtrate was concentrated on a steam bath to a volume of about 125 ml and cooled to effect crystallization. After 20 hours at room temperature the crystals that had formed were recovered, washed with isopropyl alcohol, and dried, yielding 15.61 grams (46.2%) of crystalline 5-[bis(2-hydroxy-ethyl)amino] uracil having a MP of 157° to 163°C. An analytical sample, obtained by several recrystallizations from isopropyl alcohol, melted at 166° to 168°C. 

Deprotonation provides the necessary electron push to kick out the electron pair joining C(6) with the nitrobenzene oxygen. If, however, N(l) is alkylated (as with the nucleosides and nucleotides), OH catalysis is much less efficient since it now proceeds by deprotonation from N(3) (with the uracils) or from the amino group at C(4) (with the cytosines). In these cases the area of deprotonation is separated from the reaction site by a (hydroxy)methylene group which means that the increase in electron density that results from deprotonation at N(3) is transferable to the reaction site only through the carbon skeleton (inductive effect), which is of course inefficient as compared to the electron-pair donation from N(l) (mesomeric effect) [26]. Reaction 15 is a 1 1 model for the catalytic effect of OH on the heterolysis of peroxyl radicals from pyrimidine-6-yl radicals (see Sect. 2.4). 

Thymine derivatives - 5-[7V-(2-Amino-4-hydroxy-6-methyl-5-pyrimidinyl-propyl)-p-carboxyanilinomethyl] uracil (XXXIII) was synthesized for study as a possible intermediate in the enzymatic synthesis of thymidylate. It is active as an enzyme inhibitor against thymidylate synthetase isolated from E. coli [298]. Certain thymine derivatives containing a 2-thioimidazole moiety (XXXIV, R = alkyl) inhibit growth of Ehrlich ascites carcinoma (fluid form) in mice [299]. 

An amino or hydroxy group facilitates 5-bromination even in aqueous solution. A -bromosuccinimide (NBS) and molecular bromine are the commonest reagents used. In uracils, cytosines, and barbituric acids, products of both addition and substitution can be identified in aqueous solution, and 5,5-dibromo products are common. In the bromination of uracils, addition products, including covalent hydrates, form rapidly, and the acid-catalyzed dehydration step to 5-bromouracils is much slower. Cytosine and related compounds behave similarly <1994HC(52)1, 1996CHEC-II(6)93>. 

Cytosine (2-hydroxy-6-amino-pyrimidine), uracil (2,6-dihydroxypyrimidine), and thymine (5-methyluracil) are pyrimidine derivatives adenine (6-aminopurine), guanine (2-amino-6-hy-droxypurine), and xanthine (2,6-dihydroxypurine) are purine derivatives (Fig. 5). 

Fig. 15.1. The four bases found in the nucleic acids. Uracil occurs in RNA and is substituted by the analogous thymine (5-methyluracil) in DNA. Uracil is the keto tautomer of 2,4-dihydroxy pyrimidine with two donors N(1)H, N(3)H and two acceptors 0(2), 0(4). Cytosine is the keto tautomer of 4-amino, 2-hydroxy pyrimidine with three donors N(4)H2, N(1)H and two acceptors 0(2), N(3). Adenine is 6-aminopurine with three donors N(6)H2, N(9)H and three acceptors N(l), N(3), N(7). Guanine is the keto tautomer of 2-amino, 6-hydroxy purine with three donors N(2)H2, N(9)H and three acceptors, N(3), N(7), 0(6). In the nucleosides, pyrimidine N(l) and purine N(9) are substituted by ribose or deoxyribose (see Fig. 17.1)...

Solvent-free condensation of malonic acid or cyanoacetic acid and ureas in the presence of acetic anhydride under MW irradiation conditions affords functionalized uracil derivatives such as 6-hydroxy or 6-amino uracils in high to excellent yields (Scheme 8.76) [188]. 

Cysteine had also been found to add photochemically to poly U, poly C, and DNA, thus adding credence to Smith and Aplin s postulate that the formation of a heterodimer between a pyrimidine and a sulfur (or hydroxy) amino acid may constitute a mechanism for the photochemical cross-linking of DNA and protein in vivo (Smith, 1962, 1964 Smith et al, 1966). Infrared data suggested that the COOH and amino groups of the cysteine residue were free, implying that the linkage to the uracil skeleton was through the sulfur bond. 

The 3"-hydroxy group and the amino group of the aminoribosyl-glycyluridine and the uracil moiety are essential for the inhibition of E. coli franslocase I. 

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