Of uracil

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. 

Nikkomycins. The nikkomycins (141—159), isolated from S. tendae are nucleoside-peptide antibiotics (1,4,244,245) as shown in Table 8. Nikkomycins X and Z are stmcturaHy identical to neopolyoxins A and C, respectively. Compound (141) is a competitive inhibitor of chitin synthetase. Two new nikkomycins, nikkomycin pseudo-Z and pseudo-J (158, 159), contain a C-glycosidic bond between C-5 of uracil and C-1 of... 

Such calculations have been made also for pyrimidines of biological interest (B-60MI21302). That for uracil (5) is interesting in that a figure of -0.22 is assigned to the 5-position, compared with almost zero in pyrimidine this immediately explains the ease of electrophilic attack at the 5-position of uracil as well as the lack of nucleophilic activity at the same position. 

The direct formation of dipyrimidin-5-yl sulfides occurs on treatment of appropriate 5-unsubstituted pyrimidine substrates with sulfur mono- or di-chloride. Thus, reaction of uracil (83 R = H) with sulfur monochloride in boiling formic acid gives diuracil-5-yl sulfide in good yield sulfur dichloride gives a poor yield. Simple derivatives of uracil and barbituric acid undergo similar reactions but not cytosine, isocytosine, 2,4-bismethylthiopyrimidine or pyrimidine-4,6-dione (59). The mechanism is unknown (72AJC2275). 

In contrast, the photochemistry of uracil, thymine and related bases has a large and detailed literature because most of the adverse effects produced by UV irradiation of tissues seem to result from dimer formation involving adjacent thymine residues in DNA. Three types of reaction are recognizable (i) photohydration of uracil but not thymine (see Section 2.13.2.1.2), (ii) the oxidation of both bases during irradiation and (iii) photodimer formation. 

The direct introduction of an alkythio substituent into the 5-position of uracils and analogous pyrimidines is possible. The reagent, which is usually made quite easily in situ,... 

Uracil reacts with hydrazine to give pyrazol-3(2if)-one (944) and urea N-methyl- and dimethyl-hydrazine behave similarly to give the 2-methyl- and 1,2-dimethyl derivatives. The reactions of hydrazines with uridine and related nucleosides and nucleotides is well studied (67JCS(C)1528). The tautomerism and predominant form of uracil are discussed in Section 2.13.1.8.4. 

Having a 5-methyl group, thymine is not nitrated or halogenated normally, but with aqueous bromine it does give the dihydropyrimidine (948) (25JBC(64)233) its other reactions parallel those of uracil although its behavior on irradiation is somewhat different (Section 2.13.2.1.4). 

There are many synthetic routes to alloxan. Probably the best is direct oxidation of barbituric acid (1004 R = H) with chromium trioxide (5208(32)6) but it may be made from barbituric acid via its benzylidene derivative by direct or indirect oxidation of uric acid from 5-chlorobarbituric acid (1004 R = C1) by nitration or from 5-nitrobarbituric acid (1004 R = N02) by chlorination, both via the intermediate (1005) (64M1057) or by permanganate oxidation of uracil (1006) under carefully controlled conditions (73BSF1167). 

A required step for the in vivo incorporation of uracil into DNA is the... 

FIGURE 11.28 The 5-methyl group on thymine labels it as a special kind of uracil. 

The names of these compounds as aza analogs were coined in the same way as those of the 6-aza analogs employing the frequently used numbering of uracil (1). This nomenclature is most often used for the principal aza analogs of pyrimidine bases (e.g., 5-azauracil) it is rarely used for further systematic derivatives. 

It should be mentioned that a similar comparison of the dissociation constant values of uracil monoalkyl derivatives does not permit the determination of the sequence of dissociation on account of the small differences between the pEo values. However, the pH dependence of the XJV spectra showed that the first dissociation of uracil occurs at the NH group in position 1 and thus differently than in 6-azauracil. This, together with different acidity, represents the main differences between the properties of uracil and its 6-aza analogs. 

Acetylation of 6-azauracil thus proceeds in the same way as the acetylation of uracil and the properties of the acetyl derivatives are also roughly identical. 

It may be said in conclusion that the reactivity of position 5 (i.e., 6 of the triazine ring) is similar to that of uracil. The only difference seems to be in the failure to prepare 5-nitro-6-azauracil although this reaction proceeds readily with uracil. 

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]. 

The substituent effects on the H-bonding in an adenine-uracil (A-U) base pair were studied for a series of common functional groups [99JPC(A)8516]. Substitutions in the 5 position of uracil are of particular importance because they are located toward the major groove and can easily be introduced by several chemical methods. Based on DFT calculation with a basis set including diffuse functions, variations of about 1 kcal/mol were found for the two H-bonds. The solvent effects on three different Watson-Crick A-U base pairs (Scheme 100) have been modeled by seven water molecules creating the first solvation shell [98JPC(A)6167]. 

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