Purine from 5-aminoimidazole-4-carboxamide

Purine bases from ingested foods, or formed by cafabolism of nucleic acids, are able to reacf with PRPP under the influence of phosphoribosylfransferases. Two such enzymes are known to acf on purines. One converfs adenine to AMP (Fig. 25-17, sfep b) and also acfs upon 5-aminoimidazole -carboxamide. This enzyme may be especially imporfanf to parasitic protozoa such as Leishmania, which lack the de novo pathway of purine synthesis (Fig. 25-15). ... 

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. 

All the carbon atoms of the purine ring were supposedly provided by HCN molecules through a complex step-by-step condensation process. In particular, oligomers of HCN, such as the HCN-trimer aminomaleonitrile (AMN) and the HCN-tetramer diaminomaleonitrile (DAMN), were found to be intermediates in this transformation (Scheme 1) [43,44]. In accordance with the present-day biosynthesis of purines in the cell, two 4,5-di-substituted imidazole derivatives, 4-aminoimidazole-5-carbonitrile (AICN) and 4-aminoimidazole-5-carboxamide (AICA) were successively formed from AMN and DAMN by chemical or, most probably, photochemical reactions [45-47]. Finally, a ring-closure process of AICA and HCN yielded adenine 1. 

Almost all recorded purine syntheses from imidazoles involve the cyclization of 5(4)-aminoimidazole-4(5)-carboxylic acid derivatives especially the carboxamides, thiocar-boxamides, carboxamidines, carboxamidoximes, nitriles and esters. The intermediates used for completion of the purine ring are much the same as have been used for Traube cyclization of diaminopyrimidines (Section 4.09.7.3), especially formic and carbonic acid derivatives, and cyclization generally occurs-under much milder conditions. This feature has been of special value in the synthesis of purine nucleosides from imidazole nucleoside precursors. The resultant purine will have variable substituents at C-2 and C-6 and it is convenient to discuss and classify the various preparations largely in terms of the introduced 2-substituents. The C-6 substituents largely reflect the type of carboxylic acid moiety used and do not vary very much between amino, oxo and thioxo. 

Ethyl acetate and ethyl propionate in ethanolic sodium ethoxide with 5-aminoimidazole-4-carboxamide and its riboside have provided a route to 2-methyl- and 2-ethyl-hypoxanthine arid corresponding 2-alkylinosines, respectively (67JOC3258,68JA2661). 2-Methylhypoxan-thine has also been prepared from the same imidazole and ethyl orthoacetate via an intermediate ethoxymethylene derivative which cyclized to the purine when heated (60JA3144). The same method has been applied to the synthesis of 2,8-dimethyl- and XS-diphenyl-hypoxanthine from appropriate imidazole precursors. 

Histidine is derived from three biomolecules PRPP (five carbons), the adenine ring from ATP (one nitrogen and one carbon), and glutamine (one nitrogen). The ATP used in the first reaction in the pathway is regenerated when 5-phosphoribosyl-4-carboxamide-5-aminoimidazole (released in a subsequent reaction) is diverted into the purine nucleotide biosynthetic pathway. 

Other successful uses of triethyl orthoformate include formation of pteri-din-4-ones from 2-aminopyrazine-3-carboxamide (see 9) and its derivatives127,229 233 234 cis- and trans-4a,5,6,7,8,8a-hexahydroquinazolin-4-ones from the related 2-aminocyclohexanecarboxamides61,65 pyrido[2,3-d]pyri-midin-4-ones (see 3) from 2-aminopyridine-3-carboxamide235 thiazolo[5,4-d]pyrimidin-4-one (see 148) from 5-aminothiazole-4-carboxamide236 and purin-6-ones (see 19) from 4-aminoimidazole-5-carboxamide.232,237 Any partial acetylation of 7c-excessive products can be reversed by a final alkaline treatment.238... 

Phenyl thiochloroformate (CICOSPh) has been used to produce purine-2,6-diones in good yields from 4-aminoimidazole-5-carboxamide and its derivatives phenylmercaptan is evolved.201... 

In some cases, purines are prepared from 4,5-disubstituted imidazoles by cyclocondensation with formic acid or its equivalents, e.g. the 9-alkylpurin-6(l//)-one 20 fi om l-alkyl-5-aminoimidazole-4-carboxamide 19 and formic acid ... 

As indicated above, derivatives of folic acid play a key role in the biosynthesis of purines and pyrimidines. These pteridines are the coenzymes responsible for inserting the carbon atoms into both positions 2 and 8 of purines, and they also insert the methyl-group into thymine (4.7 ). When bacteria are treated with low concentrations of sulfonamides, 4-aminoimidazole-5-carboxamide ribotide 9.22) accumulates in the culture media. This substance is an intermediate in the biosynthesis of inosinic acid 9.23) from which all purines are derived. 

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. 

---