6-Diazo-5-oxo-L-norleucine

Chemistry

DON is a water-soluble yellowish powder, which can be dissolved also in aqueous solutions of methanol, acetone or ethanol, but dissolution in absolute alcohols is difficult. Solutions of at least 50 μM DON in 0.9% NaCl are lightly yellowish. The crystalline form appears as yellowish greenish needles. The specific rotation is [α]26D +21° (c = 5.4% in H2O). In phosphate buffer, pH 7 are the ultraviolet absorption maxima at 274 nm (E1%1 cm. 683) and 244 nm (E1%1 cm 376).

Biochemistry

DON is used as inhibitor of different glutamine utilizing enzymes. Due to its similarity to glutamine, it can enter catalytic centres of these enzymes and inhibits them by covalent binding, or more precisely, by alkylation. The following table gives a survey of DON targets.

Pharmacology

DON is a cytotoxic inhibitor of many enzymes of nucleotide synthesis. It could be shown in vitro that DON treatment led to apoptosis, or programmed cell death. Different pathways were investigated; it could be shown that the inner mitochondrial membrane was damaged, and that single strand DNA breaks occurred. The exact mode of action remains unclear and needs further research.

DON has not been approved as a pharmaceutical agent; however, it has been tested in combination with a recombinant glutaminase in clinical trials for the treatment of different solid tumors.

References

References

1. "CID 5359375". United States National Library of Medicine.
2. (April 2021). "Complete Biosynthetic Pathway of Alazopeptin, a Tripeptide Consisting of Two Molecules of 6-Diazo-5-oxo-l-norleucine and One Molecule of Alanine". Angewandte Chemie.
3. (1954). "6-diazo-5-oxo-L-norleucine, A new tumor inhibitory substance. II: Isolation and Characterization".
4. (June 1992). "Glutamine antagonist with diet deficient in glutamine and aspartate reduce tumor growth". The Tokushima Journal of Experimental Medicine.
5. (29 May 2019). "Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma". Communications Biology.
6. (August 1958). "6-Diazo-5-oxo-L-norleucine, a New Tumor-inhibitory Substance.^1a Preparation of L-, D- and DL-Forms^1b". Journal of the American Chemical Society.
7. (February 2000). "Reactions of Pseudomonas 7A glutaminase-asparaginase with diazo analogues of glutamine and asparagine result in unexpected covalent inhibitions and suggests an unusual catalytic triad Thr-Tyr-Glu". Biochemistry.
8. (1977). "Affinity labeling".
9. (1 January 1958). "Pyrimidine Studies: I. Effect of DON (6-Diazo-5-oxo-l-norleucine) on Incorporation of Precursors into Nucleic Acid Pyrimidines". Cancer Research.
10. (March 1957). "Biosynthesis of the purines. XV. The effect of aza-L-serine and 6-diazo-5-oxo-L-norleucine on inosinic acid biosynthesis de novo". The Journal of Biological Chemistry.
11. (1990). "Metabolism and action of amino acid analog anti-cancer agents". Pharmacology & Therapeutics.
12. (February 1966). "Effects of 6-diazo-5-oxol-norleucine and other tumor inhibitors on the biosynthesis of nicotinamide adenine dinucleotide in mice". Cancer Research.
13. (August 1976). "DON, CONV and DONV-II. Inhibition of L-'asparagine synthetase in vivo". Biochemical Pharmacology.
14. (July 1999). "A mechanism behind the antitumour effect of 6-diazo-5-oxo-L-norleucine (DON): disruption of mitochondria". European Journal of Cancer.
15. (June 1996). "DNA strand cleavage by tumor-inhibiting antibiotic 6-diazo-5-oxo-L-norleucine". Mutation Research.
16. (2008). "A phase IIa study of PEGylated glutaminase (PEG-PGA) plus 6-diazo-5-oxo-L-norleucine (DON) in patients with advanced refractory solid tumors". J Clin Oncol.