Glutamine antagonist

One example of a naturally occurring diazirine, duazomycin A (137 Scheme 11.20), has been reported, isolated in 1985 from a Streptomyces species during a screen for herbicidal compounds [196], It was fotind to inhibit de novo starch synthesis and it was suggested that this is due to direct inhibition of protein synthesis. Duazomycin A is structurally related to 6-diazo-5-oxo-L-norleucine (138), also reported as a natural product from Streptomyces [197], which acts as a glutamine antagonist and inhibits purine biosynthesis [198],... 

A series of anti-metabolites have also been prepared which contain an alkylating moiety to enable the antagonists to inhibit the appropriate enzyme irreversibly, by formation of a co-valent bond94. Two compounds of this type to have had a clinical trial are the glutamine antagonists azaserine 44 and 6-diazo-5-oxo-L-norleucine (DON 45). 

Thus, a large number of substances have been tested as inhibitors for the steps in purine and pyrimidine metabolism (Cory, in Devlin, 1986, p. 674 0. Inclnded are both synthetic compounds and compounds isolated from plants, bacteria, fungi, etc. The substances may be further classed as glutamine antagonists, antifolates, and antimetabolites. Whereas the first-mentioned substances are toxic in the extrane, the latter two classifications have been of main concern although they are toxic enough in their own right. 

Two of the more important purine analogs in use clinically are 6-mercaptopurine and 6-thioguanine. These purine antagonists and glutamine antagonists such as azaserine (Table 4-6) are major antagonists in the biosynthesis of purine bases. Before understanding the mechanism of their action, it is necessary to look at the biosynthesis of inosinic acid, the purine ribonucleotide that is the precursor to both purine bases found in DNA and RNA... 

Azaserine, a glutamine antagonist," is known to inhibit the NAD synthetase reaction in which nicotinic acid adenine dinucleotide is converted into NAD with glutamine or ammonia as the nitrogen donor. ° When azaserine or azaleucine was fed to Ricinus communis plants followed by [6- C]quinolinic acid, a marked decrease in incorporation of radioactivity into ricinine was observed with azaleucine, less so with azaserine." Both azaserine and azaleucine were found also to inhibit the incorporation of [6- " C]quinolinic acid into pyridine nucleotide cycle intermediates [in the case of azaserine the conversion of nicotinic acid dinucleotide into nicotinamide adenine dinucleotide (NAD ) was apparently inhibited]. 

The amino acid antagonists broadly act as a glutamine antagonists in the synthesis of formylglycinamidine ribotide from glutamine and formylglycinamide ribotide. 

The drug is believed to be a glutamine antagonist that specifically inhiits purine biosynthesis and thus may exert antitumour activity. 

Other Antimetabolites - The suggestion has been made that the cytotoxic effect of azaserine, the glutamine antagonist, may be due to the depletion of adenine nucleotides that act as activators of thymidine and thymidylate... 

In several studies of the L-glutamine D-fructose 6-phosphate amidotransferase reaction it has been shown that specific glutamine antagonists may be used to inhibit the reaction. Ghosh et al. (1960) showed that 6-diazo-5-oxo-L-norleucine (DON) was a potent inhibitor of the enzyme, whereas azaserine was less effective. The glutamine analogs, methionine sulfoxide and y-glutamyl hydrazide, on the other hand, were not inhibitory (Clarke and Pasternak, 1962). 

C5H7N3O4, Mr 173.13. Light yellow to greenish cryst., mp. 153-155°C (decomp.), [a]p +9.T (2 N HCI). A. is an antibiotic, isolated in optically active L-form, from Streptomyces species, the racemic form can be synthesized. As antagonist of glutamine it has mutagenic, bactericidal, fungicidal, and cytostatic activities. 

By the thymineless death method a situation is created in which the parental cells die and the mutant cells do not grow but are able to stay alive in the selective environment. Since mammalian cells utilize thymidine instead of thymine, a state of thymidine starvation is created by exposing cells to a folic acid antagonist, such as aminopterin. Under these conditions, the prototrophs continue to grow until death, while the auxotrophs do not grow but remain alive and can thus be rescued. This method has been successfully applied to isolation of glutamine-requiring mutant lines from HeLa cells (De Mars and Hooper, 1960) and Chinese hamster cells (Chu et aLy 196%). 

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