6- diazo-5-oxo-L-norleucine

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],... 

Nitrogen can be transferred from glutamine into many other substrates.102 Several antibiotic analogs of glutamine have been useful in studying these processes. Examples are the streptomyces antibiotics L-azaserine and 6-diazo-5-oxo-L-norleucine (DON). 

Two other residues which have been modified by affinity labels containing diazo linkages are sulfhydryl groups and histidine. Hartmann (1963) has shown that 6-diazo-5-oxo-L-norleucine (XXII),... 

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). 

Dion HW, Fusari SA, Jakubowski ZL, Zora JG, Bartz QR. 6-diazo-5-oxo-L-norleucine, a new tumor inhibitory substance 1. Isolation and characterization. J. Am. Chem. Soc. 78 3075-3077, 1956. 

Kisner DL, Catane R, Muggia FM. The rediscovery of DON (6-diazo-5-oxo-L-norleucine). Recent results. Cancer Res 74 258-263, 1980. 

Levenberg B, Melnick O, Buchanon JM. Biosynthesis of the purines. XV. The effect of aza-L-serine and 6-diazo-5-oxo-L-norleucine on the inosinic acid biosynthesis de novo. J. Biol. Chem. 225 163-176, 1957. 

Ovejera AA, Houchens DP, Catane R, Sheridan MA, Muggia FM. Efficacy of 6-diazo-5-oxo-L-norleucine and N-[N-gamma-glutamyl-6-diazo-5-oxo-norleucinyl -6-diazo-5-oxo-norleu-cine against experimental tumors in conventional and nude mice. Cancer Res. 39(8) 3220-3224, 1979. 

Alazopeptin, L-A]anyl-(6-diazo-5-oxo -i-nor-leucy -(6-diazo-5-oxo)-l-norleucine, CisH NjO, mol wt 364.37. C 49.45%, H 5.53%, N 23,06%, 6 21,96%. Tumor-inhibiting antibiotic produced by Streptomyces griseoplatttts from soil near Williamsburg, Iowa De Voe et al. Am thiol... 

Approaches to the syntheses of the Streptomyces anticancer antibiotics 6-diazo-5-oxo-L-norleucine (73 DON) and azotomycin... 

Azaserine (O-diazoacetyl-L-serine) and 6-diazo-5-oxo-L-norleucine (DON) and L-2-amino-3-ureidoproprionic acid (albizziine) are inhibitors of a wide range of glutamine using enzymes in which the amide-amino group is transferred. 

Another common feature of the amidotransferases is that they are inhibited by the antibiotics azaserine (0-diazoacetyl-L-serine) and 6-diazo-5-oxo-L-norleucine when glutamine is substrate. However, these compounds are much less inhibitory when NH3 is the nitrogen donor. Recently two new glutamine analogues have been introduced, 2-amino-4-oxo-5-chloro-pentanoic acid 2) and albizziin 8). The structures of these compounds are given in Fig. 5-3. 

Diazo-5-oxo-L-norleucine (I) and 0-diazoacetyl-L-serine (II) were originally isolated from Streptomyces fermentations, shown to have anti-... 

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). 

The glutamine analog 6-diazo-5-oxo-L-norleucine (DON) inhibits L-glu-tamine n-fructose-6-phosphate amidotransferase (Section III) in the-pathway of conversion of C-glucose to both sialic acid and N-acetylga-lactosamine and, as expected, thereby inhibits incorporation of C-glu-cose into OSM. With glucose as the sole carbohydrate source in the incubation medium, DON also inhibits incorporation of radioactive amino acids into OSM but causes a concomitant increased incorporation of labeled amino acid into other protein fractions these latter proteins may contain nonglycosylated polypeptide precursors of OSM. All the inhibitory effects of DON are prevented if glucosamine is present in the incul ition medium. 

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