Pyrimidine Azauracil

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. 

The chemistry of the 6-aza analogs of pyrimidine bases which has been developed from the biochemical aspect since about 1956 was based on work reported in relatively numerous older papers. In spite of the fact that 6-azauracil was prepared only in 1947 and suitable syntheses were described only quite recently, substances of this type and methods of their preparation had been known for a long time. The chemistry of 6-aza analogs of pyrimidine bases is therefore relatively closely linked with the chemistry of the 1,2,4-triazine derivatives. 

Ketofucosyl nucleosides (38a and 38b) of 5-fluorouracil and 6-azauracil have been obtained39 from the partially protected L-fucosyl-pyrimidines 37a and 37b by oxidation with Me2SO-DCC and Ru04-CHC13, respectively. 

Other selective therapeutants are carboxin, several pyrimidines, triforine, several morpholines, 6-azauracil, azepines, phenylthioureas, chloroneb, and others. 

These experiments suggest that, in the presence of 6-azauracil, there is a block in the utilization of pyrimidines at the nucleotide level. Later experiments have shown that there is an inhibition of orotidylic decarboxylase... 

Both 5-hydroxyuracil (isobarbituric acid, I) and 5-hydroxyuridine (II) can be prepared from the corresponding 5-bromopyrimidines by mild basic hydrolysis [5-8]. 5-Hydroxyuracil inhibits enzymatic degradation of uracil [9] and is one of three pyrimidine analogues (the other two are 5-bromouracil and 6-azauracil) that inhibit the rate of incorporation of uracil into nucleic... 

C30 Cihak, A. and Sorm, F. Metabolic transformations of 5-azauracil and 5-azaorotic acid in mouse liver and Escherichia coli. Effect on the synthesis of pyrimidines. Biochem. Pharmacol., 21, 607-617 (1972)... 

It is well established that aza analogs of purines, pyrimidines and their nucleosides possess significant but varying potency as antineoplastic agents [1-7]. Thus, for example, 6-azacytidine is an inhibitor for orotidylic acid decarboxylase [3] and 6-azauracil inhibits the development of animal tumors [4] and human acute leukemia [5] similarly, 8-azaguanine is a highly effective anti-neoplastic agent [6] and also inhibits animal tumors [7]. 

Cytidine has been converted into l-(5-amino-5-deoxy-j8-D-arabinofuranosyl) cytosine by a sequence of reactions involving A-benzoylation, sulphonation, acetylation, displacement with azide ion, e/c., and l-(3-amino-3-deoxy-jS-D-arabinofuranosyl)-6-azauracil was derived from 2, 3 -di-0-methanesulphonyl-5 -O-trityl-6-azauridine via 2,2 - and 2, 3 -anhydro-nucleosides. Other syntheses have been accomplished by the condensation of an appropriately derivatized amino-sugar with either a pyrimidine or purine derivative for example, the Hilbert route was used to prepare l-(2-amino-2-deoxy-a-D-arabino- and -jS-o-xylo-furanosyl)cytosine. > The reactivity of l,3,4,6-tetra-0-acetyl-2-acyl-amido-2-deoxy-j3-D-glucopyranoses in condensation reactions with 2,6-dichloro-purine, theophylline, and 6-benzylaminopurine was shown to be in the order benzamido > acetamido > phthalimido. 9-(3-Acetamido-2,5-di-0-acetyl-3-deoxy-j8-D-ribofuranosyl)-2,6-dichloropurine has been synthesized and converted into the corresponding 2,6-diamino- and 6-amino-2-chloro(fluoro)-nucleosides. ... 

The first chemical synthesis of these substances, using a procedure which yields 1-ribofuranosyl derivatives by pyrimidine bases, was described by Hall. By using the mercuric salt of 6-azathymine and tribenzoate of D-ribofuranosyl chloride, he obtained a mixture of two raonoribosyl derivatives and a diribosyl derivative. He determined the structure of the 3-substituted derivative by the similarity of spectra and other properties to those of 3-methyI-6 azauracil. The structure of the 1-ribosyl derivative was then determined from the similarity of the spectra with 6-azathymine deoxyriboside obtained enzymatically. 

Chemical and enzymatic ribosidization of the aza analogs of the pyrimidine bases thus take different routes. These results and inde-p>endent earlier studies of the alkylation of 6-azauracil led to the conclusion that, in order to achieve ribosidization in position 1 (i.e., position 2 of the triazine ring), the position 3 (4 of the triazine ring) must be protected. ... 

Many potent pyrimidine antagonists have also been obtained by isosteric replacement in the heterocyclic ring. Oxonic acid (Fig. 12) an analogue of orotic acid, prevents the conversion of the latter to orotidylic acid (Fig. 2). A later stage of pyrimidine biosynthesis, the decarboxylation of orotidylic acid to form uridylic acid (Fig. 2) is strongly inhibited by 6-azauracil (Fig. 12 this chemical should be correctly termed 4-azauracil). The riboside of 6-azainacil acts on the same pathways as the base, but its inhibition of the orotidylate carboxylase enzyme is some 20 times more potent... 

Dipple A, Heidelbetger C (1966) Fluorinated pyrimidines. XXVIII. The synthesis of 5-trifluoromethyl-6-azauracil and 5-trifluotomethyl-6-aza-2 -deoxyuridine. J Med Chem 9 715-718... 

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