Formate 5-amino-4-imidazole carboxamide

Under physiological conditions the pathway of purine biosynthesis de novo is believed to be irreversible. Reversibility of some reactions can, however, be demonstrated under some conditions of incubation in vitro. If Ehrlich ascites tumor cells are incubated with formate- C in the absence of glucose, for example, the 2-position of the purine ring may contain 8 to 10 times as much C as does the 8-position (SO), although these two positions should be equally labeled if net synthesis only had occurred. Apparently inosinate can be reversibly converted to phosphoribosyl amino-imidazole carboxamide, which in reforming inosinate incorporates radioactive formate. 

A simple and efficient synthesis of 9-substituted guanines by cyclodesulfurization of 1-substituted 5-[(thiocarbamoyl)amino]imidazole-4-carboxamides under aqueous basic conditions has been described, e.g. formation of 9-methylguanine 12. °... 

Adenylosuccinate formed by adenylosuccinate synthetase is cleaved by adenylosuccinate lyase to form AMP. The reaction steps are illustrated in Fig. 1. Included in the sequence is the additional reaction catalyzed by AMP deaminase. These three enzymes have been suggested to function in a cyclic process termed the purine nucleotide cycle 7,8). The two-step conversion of IMP to AMP is very similar to both the conversion of citrulline to arginine, which involves formation of argininosuccinate as an intermediate, and formation of 5-amino-imidazole 4-carboxamide ribonucleotide from 5-aminoimidazole 4-carboxylate ribonucleotide as part of IMP biosynthesis. Adenylosuccinate lyase is a dual function enzyme catalyzing the cleavage of both adenylosuccinate and 5-aminoimidazole 4-N-succinocarboxamide ribonucleotide. 

Amino-4-imidazole carboxamide ribotide, a precursor only two steps removed (formylation and cycli-zation) from inosinic acid, can be synthesized by the direct condensation of the imidazole with 5-phosphori-bosyl pyrophosphate. The enzyme catalyzing this reaction was purified from an acetone powder of beef liver. The same enzyme (AMP pyrophosphorylase) catalyzes the condensation of adenine, guanine, and hypoxan-thine. Nucleoside phosphorylase is an enzyme that catalyzes the formation of a ribose nucleoside from a purine base and ribose-1-phosphate. Guanine, adenine, xanthine, hypoxanthine, 2,6-diaminopurine, and aminoimidazole carboxamide are known to be converted to their respective nucleosides by such a mechanism. In the presence of a specific kinase and ATP, the nucleoside is then phosphorylated to the corresponding nucleotide. 

In summary, the biochemical function of folate coenzymes is to transfer and use these one-carbon units in a variety of essential reactions (Figure 2), including de novo purine biosynthesis (formylation of glycinamide ribonucleotide and 5-amino-4-imidazole carboxamide ribonucleotide), pyrimidine nucleotide biosynthesis (methylation of deoxyuridylic acid to thy-midylic acid), amino-acid interconversions (the interconversion of serine to glycine, catabolism of histidine to glutamic acid, and conversion of homocysteine to methionine (which also requires vitamin B12)), and the generation and use of formate. 

Then the amino group of aspartate is transferred to the carboxyl, making an amide. This condensation uses ATP and the amide is cleaved to release fumarate, leaving behind the imidazole with a 5-amino group (left from the amidation of glycine four steps earlier) and a 4-carboxamide. (Note how this reaction is similar to the formation of arginine during the urea cycle.)... 

Purine 9-oxides on the other hand are best made from imidazole precursors. Thus 9-hydroxy-8-methylxanthine (368) and hypoxanthine (369) have been most conveniently obtained by cyclization of 5-amino-l-benzyloxy-2-methylimidazole-4-carboxamide (370) with carbonate or formate esters, respectively, and debenzylation of the intermediate benzyloxy derivatives with hydrogen bromide in acetic acid (Scheme 156) (72JOC1867). 

The method for preparation of, V -aryladenines employs 5-acetamido-l//-imidazole-4-carbox-amide hydrochloride, which can be obtained by simple acetylation of commercially available 5-amino-l//-imidazole-4-carboxamide hydrochloride (AlCA HCl), e.g. formation of 21. ... 

Trifluoromethylpurines have been prepared mainly through formation of the pyrimidine ring starting from highly functionalised imidazoles. 5-Amino-4-(cyanoformimidoyl)imidazole 29 reacted rapidly with neat trifluoroacetic anhydride to give the 6-cyano-2-trifluoromethylpurine 30 (20 °C, 10 min, 52 %) [55] (Scheme 13). However, hydrolysis to the 6-carboxamidopurine 31 was observed when the reaction was carried out over several days [55,56]. This latter transformation has been applied to prepare 9-(3-hydroxy-propyl)-2-trifluoromethyl-9H-purine-6-carboxamide [57]. 

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