5- imidazole-4-carboxamide

IMP, is synthesised with mutants of Bacillus subtilis or Corynehacterium am-moniagenes. Xanthosine 5 -monophosphate is produced with Corynebacte-rium or Bacillus and subsequently converted into GMF by Bacillus and other strains [6]. Alternatively, another related compound, 5 -amino-4-imidazole carboxamide-l-riboside-5 -phosphate, is produced by Bacillus megaterium and chemically converted into GMP [22, 36],... 

Small quantities of the 5-amino-4-imidazolecarboxamide nucleotide were also isolated from the culture medium of Escherichia coli grown under sulfonamide bacteriostasis.i i This substance is considered to be an intermediate in purine biosynthesis, both in micro-organisms and in mammalian cells. In sulfonamide-inhibited cells and in the purine-requiring mutant of Escherichia coli, there is a block in the conversion of 5-amino-4-imidazole-carboxamide n-ribonucleotide to inosinic acid. The accumulated nucleotide in the bacterial cell is probably attacked by phosphatases this would explain why the nucleoside is the main metabolite. 

Temozolomide is one of a series of imidazoletetrazine derivatives that was developed as a potential alternative to dacarbazine. Temozolomide is a prodrug of the active metabolite of dacarbazine. Dacarbazine requires hepatic transformation to its active intermediate, whereas at physiologic pH, temozolomide chemically degrades to the cytotoxic triazene monomethyl 5-triazeno imidazole carboxamide. Temozolomide is administered orally and appears to be less emetogenic than dacarbazine. Temozolomide appears to cross into the central nervous system, and therefore was initially thought to have benefit for patients with CNS metastases. In chemotherapy-naive individuals with metastatic melanoma, response rates for temozolomide are similar to those seen with dacarbazine. 

Inosine can be converted directly to inosinate by inosine kinase. This enzyme has been shown to exist in human cells, but at a low level (P2). It undoubtedly does not play a major role. Inosine phosphorylase cleaves inosine to hypoxanthine and ribose I-phosphate (Kl). Inosine is formed by the deamination of adenosine catalyzed by adenosine deaminase, an enzyme found in varying concentrations in essentially all normal mammalian cells examined. Studies with an inhibitor of adenosine deaminase, ribosyl-4-amino-5-imidazole carboxamide, on several strains of Escherichia coli revealed a major role for the enzyme. In cells with a block in purine synthesis a condition of guanine deprivation occurred after growth with adenine as purine source, and there was a derepression of the enzymes that convert IMP to XMP and XMP to GMP (K17). 

Phosphoribosyl formimino-5-amino imidazole carboxamide ribonucleotide... 

Fig. 2. The pathway of histidine biosynthesis. Enzymes a, ribosephosphate pyrophos-phokinase E.C. 2.7.6.1 b, ATP-phosphoribosyltransferase, E.C. 2.4.2.17 c, phosphoribosyl-AMP cyclohydrolase, E.C. 3.5.4.19 d, N-(5 -phospho-D-ribosylforminino)5-amino-l-(5"-phos-phoribo yl)-4-imidazole carboxamide isomerase, E.C. 5.3.1.16 e, glutamine amidotransferase f, imidazolglycerolphosphate dehydratase E.C. 4.2.1.19 g, histidinol-phosphate aminotransferase E.C. 2.6.1.9 h, histidinol phosphatase, E.C. 3.1.3.15 i, histidinol dehydrogenase, E.C. 1.1.1.23.

K64 Kubonoya, J., Kimura, M. and Kongo, A. Clinical effectiveness of 4-amino-5-imidazole carboxamide orotate (Aica-min) on liver disease. Asian Med. J., 7, 196-198 (1964)... 

The heterocyclic base, 5-amino-4-imidazole carboxamide, was isolated in 1945 from sulfonamide-inhibited cultures of Escherichia coli, but its possible role as a precursor of purines was suggested only somewhat later. This re-... 

The final step in purine biosynthesis de novo is the cydization of phos-phoribosyl formamido imidazole carboxamide to form inosinate. Until... 

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. 

As mentioned in Chapter 7, adenylosuccinate lyase not only functions in purine ribonucleotide interconversion, but also converts phosphori-bosyl aminoimidazole succinocarboxamide to phosphoribosyl amino-imidazole carboxamide. Kinetic studies show that these compounds are alternative substrates and products, respectively, with adenylosuccinate and adenylate, and attempts physically to separate the two activities have consistently failed. Genetic studies have shown that both activities are governed by the same locus and that mutant enzymes behave similarly in both reactions 20, 21). 

Amino-4-imidazole carboxamide ribotide is converted to 5-formamido-4-imidazole carboxamide ribotide in a formylation reaction using N -formyltetra-hydrofolic acid. The formylation is catalyzed by 5-aminoimidazole-4-carboxamide ribotide transformy-lase. Isonicase then closes the purine ring, forming inosinic acid in the absence of ATP. Fig. 3-59 illustrates the origin of each atom of the purine ring. 

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. 

The 5-amino-4-imidazole carboxamide ribonucleotide transformylase and the glycinamide ribonucleotide transformylase reactions have been studied in chicken liver preparations by Hartman and Buchanan. 

The traditional route for the production of imidazoles, carboxamides, and sulfonamides has several disadvantages including the fact that dilute HCl is difficult to recover and that the process uses CI2. In the green route no HCl is produced and no CI2 is required (Fig. 3). If the process is coupled to the cathodic reduction of the phthalic acid dimethyl ester, phthalide can be efficiently obtained and the overall process has a 100 % atom economy [9]. 

Dichlorophenylphosphine oxide (PhPOCl2) has been applied to dehydrate variously substituted 4-imidazole carboxamides 1443 to the corresponding 4-cyano-imidazoles 1444 in yields of 82-92% [1098]. 

The corresponding hydroxyl compound, 4-hydroxy-5-imidazole-carboxamide, was also synthesized with and injected into rats. No radioactivity appeared in the respiratory CO2, nucleic acid purines, nucleotide purines, or allantoin. Apparently this substance is not active metabolically in purine synthetic reactions. 

Amino-5-imidazole-carboxamide ribotide CoF + HCOOH C -formyl-CoF O... 

Many similar reactions have been demonstrated and several hitherto unknown desoxyribosides have been enzymatically S5uithesized. The desoxyriboside of 6-methylcytosine can be formed in this way. 6-Methyl-cytosine is a component of the desoxyribonucleic acid of several animal and plant species.5-Amino-4-imidazole carboxamide also participates in reactions of this type to yield a desoxyriboside. This compound contains an incomplete purine ring and accumulates in sulfonamide-treated E. coli. It is discussed in detail elsewhere (page 229). 

Chlorobenzyl)amino)-l-(3-ethylureido)-iV, iV,5 -trimethyl- l//-imidazole -carboxamide (5c) White powder, mp 192-194 °C reaction time 7 h yield 88%... 

---