4- Aminoimidazole-5-carboxamide

Therapeutic Function Treatment of liver diseases Chemical Name 5-aminoimidazole-4-carboxamide orotate Common Name AICA orotate Structural Formula a... 

Aminoimidazole-4-carboxamide ribonucleoside (also known as AICA riboside or AICAR). An adenosine analogue that is taken up into cells by adenosine transporters and converted by adenosine kinase to the monophosphorylated nucleotide form, ZMP. ZMP is an analogue of AMP that activates the AMP-activated protein kinase (AMPK), for which acadesine or AICAR can be used as a pharmacological activator. 

The first pharmacological agent shown to activate AMPK was 5-aminoimidazole-4-carboxamide (AICA) riboside, also known as acadesine. This adenosine analogue is taken up into cells by adenosine transporters and phosphoiylated by adenosine kinase to the mono-phosphorylated form, AICA ribotide or ZMP. ZMP accumulates inside cells to higher concentrations than the concentration of AICA riboside present in the medium, and it mimics both effects of AMP on AMPK system (allosteric activation and inhibition of... 

Aminoimidazole-4-Carboxamide Ribonucleotide Transformylase Carbonic Anhydrase II DNA Gyrase... 

Aminoimidazole-4-carboxamide ribonucleotide (AlCAR) transformylase inhibitor, Ki = 154 nM, IC50 = 600 nM... 

Li C, Xu L, Wolan DW, Wilson lA, Olson AJ. Virtual screening of human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase against the NCI diversity set by use of AutoDock to identify novel nonfolate inhibitors. J Med Chem 2004 47 6681-90. 

Alkylations of 5-aminoimidazole-4-carboxamide (818) with 783 in acetonitrile and in the presence of triethylamine gave the two 1- and 3-isomers... 

Dacarbazine Dacarbazine, 5-(3,3-dimethyl-l-(riazeno)imidazol-4-carboxamide (30.6.5), is made by diazotation of 5-aminoimidazol-4-carboxamide with nitrous acid, which results in the formation of 5-diazoimidazol-4-carboxamide (30.6.4). Reacting this with dimethy-lamine gives the desired dacarbazine (30.6.5) [146]. 

Reactions of a number of l-phenylimidazole-2-carboxamides with chlorine in acetic acid, NCS, or hypochlorite failed to introduce chlorine into the 4- or 5-positions (80JHC409). Chlorination of a variety of 2,4-disubstituted imidazoles, however, was quite facile, Thus, 2,4-diesters [83JCS(P1)809] and 2-amino-4-aryl compounds [80IJC(B)526] were readily 5-chlorinated, and even when both the 4- and the 5-positions were blocked, as in 5-aminoimidazole-4-carboxamide, 2-chlorination with iodine monochloride was possible (89MI5). When all three carbons were substituted (e.g., in 2,4,5-triphenyl-, 2-chloro-4,5-diphenyl-, and 2-trichloromethyl-... 

Til. Mode of Action of Sulfa Drugs Some bacteria require p-aminobenzoate in the culture medium for normal growth, and their growth is severely inhibited by the addition of sulfanilamide, one of the earliest sulfa drugs. Moreover, in the presence of this drug, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR see Fig. 22-33) accumulates in the culture medium. These effects are reversed by addition of excess p-aminobenzoate. 

Purine bases from ingested foods, or formed by catabolism of nucleic acids, are able to react with PRPP under the influence of phosphoribosyltransferases.3063 Two such enzymes are known to act on purines. One converts adenine to AMP (Fig. 25-17, step b) and also acts upon 5-aminoimidazole-4-carboxamide. This enzyme may be especially important to parasitic protozoa such as Leishmania, which lack the de novo pathway of purine synthesis (Fig. 25-15).278/306b... 

The biosynthesis of histidine. The 5-aminoimidazole-4-carboxamide ribotide formed during the course of histidine biosynthesis is also an intermediate in purine nucleotide biosynthesis. Therefore it can be readily regenerated to an ATP, thus replenishing the ATP consumed in the first step in the histidine biosynthetic pathway (see fig. 23.13). 

PFACRI N -[(5 -phosphoribosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide isomerase ImGPS imidazole 3-glycerol phosphate synthase OMPDC orotidine 5 -phosphate decarboxylase R5PE ribulose 5-phosphate epimerase HUMPS hex-3-ulose monophosphate... 

Dacarbazine is a synthetic compound that functions as an alkylating agent following metabolic activation by liver microsomal enzymes by oxidative N-demethylation to the monomethyl derivative. This metabolite spontaneously decomposes to 5-aminoimidazole-4-carboxamide, which is excreted in the urine, and diazomethane. The diazomethane generates a methyl carbonium ion that is believed to be the likely cytotoxic species. Dacarbazine is administered parenterally and is not schedule-dependent. It produces marked nausea, vomiting, and myelosuppression. Its major applications are in melanoma, Hodgkin s disease, and soft tissue sarcomas. 

Lochhead, P. A., Salt, I. P., Walker, K. S., Hardie, D. G., and Sutherland, C. 2000. 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes 49 896-903. 

Given the above analysis and also the high cost of purchasing relatively small quantities of 5-aminoimidazole-4-carboxamide (XXIII, AIC), we in Chemical Development were given the backing to explore other possibilities and identify a safer, lower-cost route to Temozolomide that would avoid the hazards and preferably require conventional rather than specialist equipment. Another requirement, made necessary by the heavy workload in our New Jersey Chemical Development operation, was that we find an outside partner to carry out the process exploration work with us. 

Pramanik s group. He reasoned that the hydrolysis of dihydrohypoxanthine to 5-aminoimidazole-4-carboxamide (AIC) (see Scheme 19 and Figure 14 in Case Study 2) might be conveniently carried out using microwave irradiation. He dissolved dihydrohypoxanthine trifluoroacetate salt (81.1 mg) in 1 1 trifluoroacetic acid water (2 ml) and micronized the solution for 2 min at ambient pressure. After this time the electrospray-MS spectrum of the solution indicated that substantial AIC formation had occurred (Figure 1). 

Fig. 11.6. Interconversions of tetrahydrofolate derivatives. FH2 = dihydrofolic acid FH4 = tetrahydrofolic acid AICAR -= 5 aminoimidazole 4-carboxamide ribonucleotide FAICAR = formyl AICAR GAR = glycinamide ribonucleotide FGAR = formyl GAR Glu = glutamic acid FIGLU = formimino glutamic acid. (Modified from Mudd and Cantoni, 1964.)...

Fig. 13.2. Synthesis of IMP. c = Hypoxanthine phosphoribosyl transferase (HPRT) GAR = glycinamide ribonucleotide FGAR = formyl glycinamide ribonucleotide PRPP = phosphoribosyl pyrophosphate AICAR = 5 aminoimidazole-4-carboxamide...

Fig. 15-16 The de novo purine biosynthetic pathway. Rib-5-P, ribose 5-phosphate P-Rib-PP, 5-phosphoribosyl 1-pyrophosphate PRA, 5-phosphoribosylamine IO-CHO-FH4, /Vl0-formyl tetrahydrofolate GAR, glycineamide ribotide FGAR. /V-formylglycineamide ribotide FGAM, /V-formylglycineamidine ribotide AIR, 5-aminoimidazole ribotide CAIR, 4-carboxy-5-aminoimidazole ribotide SAICAR, iV-succino-5-aminoimidazole-4-carboxamide ribotide AICAR, 5-aminoimidazole-4-carboxamide ribotide FAICAR, 5-formamidoimidazole-4-carboxamide ribotide sAMP, /V-succino-AMP. Enzymes (1) amido phosphoribosyltransferase (2) GAR synthetase (3) GAR transformylase (4) FGAM synthetase (5) AIR synthetase (6) AIR carboxylase (7) SAICAR synthetase (8) adenylosuecinase (9) AICAR transformylase (10) IMP cyclohydrolase (11) sAMP synthetase (12) adenylosuecinasc (13) IMP dehydrogenase (14) GMP synthetase.

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