Aza Analogs

In general, aza substitution (replacement of cyclic CH by N) has little effect on UV spectra (Table 23). Typically, aza analogs of pyrrole show A max at 217 nm or lower with log e ca. 3.5, whereas aza analogs of thiophene show Amax at 230-260 nm with log e ca. 3.7 (Table 23) insufficient data are available for aza analogs of furan to generalize but these compounds appear to have maxima below 220 nm. 

To form a five-membered ring in this manner, the 1,3-bielectrophile must contain a heteroatom, and several systems such as the aza analog of (204) are known (68T4217,69T3453). Dimethyl AA-ethoxycarbonylthiocarbonimidate (209) reacted readily with a monosubstituted hydrazine to give the 1,2,4-triazolinone (210), and with hydroxylamine the 1,2,4-oxadiazolinone (211) was obtained (73JCS(P1)2644). 

Aza Analogs of Pyrimidine and Purine Bases of Nucleic Acids... 

An important group of antimetabolites are the aza analogs of pyrimidine and purine bases which are theoretically derived by a replacement of the methine group of a pyrimidine or purine nucleus with a nitrogen atom. This replacement represents a relatively minor alteration of the structure of these substances as it does not change the functional groups, practically preserves the molecular weight, and produces almost isosteric compounds. The replacement of the methine... 

The formal derivation of the analogs, described in the foregoing, represents, from the point of view of systematic organic chemistry, a shift to the derivatives of other heterocyclic systems. In the case of pyrimidine aza analogs we arc dealing with derivatives of symmetrical or asymmetrical triazine in the case of purine aza analogs, the derivatives produced are those of imidazo[4,5]-i -triazine and z -triazolo [4,5-d] pyrimidine. 

For this reason dual terminology is in use for the aza analogs. The first, derived from the principal pyrimidine and purine derivatives by means of the prefix aza- is used almost exclusively in biochemical papers in organic chemistry is it used together with the systematic names) wherever it is desired to compare the properties of the natural bases and of their aza analogs. The systematic terminology is naturally used in the older literature where no biochemical aspects of the compounds were considered, and in some newer work of strictly chemical nature. Since the numbering of the substituents is in some cases different for the different systems, we shall discuss this in more detail later. ... 

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 5-aza analog of cytosine could be taken as 4-amino-2-oxo-l,2-dihydro-1,3,5-triazine (40) which was prepared by the reaction of... 

In all types of nomenclature based on triazine the numbering of the substituents is shifted by one as compared with the nomenclature of 6-aza analogs of pyrimidines. 

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. 

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. 

Some of them were obtained for the first time by an enzymatic procedure which, of course, can result only in the aza analogs of natural nucleosides, i.e., ribofuranosyl-6-azauracil (6-azauridine) (75) and 2 -deoxyribofuranosyl-6-azathymine (6-azathymidine). The first of these was prepared by Skoda et ai. and a modification of their procedure was used by Handschumacher, In this way it is possible to obtain the crystalline nucleoside on the large scale. 

By comparing the dissociation constant of 6-azauracil and 6-aza-uridine with those or uracil and uridine, 6-azauridine is now considered to be 1-ribofuranosyl derivative (2-ribofuranosyl-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine), The same was shown more exactly by comparing the UV and IR spectra and the dissociation constants of 6-azauridine with the two monomethyl derivatives of 6-aza-uracil," Enzymatic synthesis thus, proceeds, in the same way in natural bases and in their aza analogs. 

Chemical and enzymatic ribosidization of the aza analogs of the pyrimidine bases thus take different routes. These results and independent earlier studies of the alkylation of 6-azauraciE 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. ... 

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