6-Diazo-5-oxo-L-norleucine

6-Diazo-5-oxo-L-norleucine
Legal status
Legal status
  • not approved
Identifiers
CAS Number 157-03-9 YesY
PubChem (CID) 5359375
ChemSpider 16735775 N
ChEMBL CHEMBL97485 N
Chemical and physical data
Formula C6H9N3O3
Molar mass 171.15 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

6-Diazo-5-oxo-L-norleucine (DON) is a glutamine antagonist, which was isolated originally from Streptomyces in a sample of Peruvian soil. It is a non-standard amino acid. The diazo compound was characterized in 1956 by Henry W Dion et al.,[2] who suggested a possible use in cancer therapy. This antitumoral efficacy was confirmed in different animal models.[3] DON was tested as chemotherapeutic agent in different clinical studies, but was never approved. The last clinical results were published in 2008, though not as DON monotherapy but in combination with a recombinant glutaminase.[4]

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).[2][5]

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.[6][7] In the following table gives a survey of DON targets.

Selection of enzymes inhibited by DON
Enzyme Metabolic pathway References
Carbamoyl phosphate synthase (CAD) Pyrimidine-De-Novo-Synthesis [6][8]
CTP synthase (CTPS) Pyrimidine-De-Novo-Synthesis [6][8]
FGAR amidotransferase Purine-De-Novo-Synthesis [6][9]
Guanosine monophosphate synthetase (GMPS) Purine-De-Novo-Synthesis [6][10]
PRPP amidotransferase Purine-De-Novo-Synthesis [6][10]
Mitochondrial glutaminase First step of glutaminolysis [6][10]
NAD synthase Coenzyme of the electron transport chain [6][11]
Asparagine synthetase Amino acid synthesis [6][12]

Pharmacology

DON is a cytotoxic inhibitor of many enzymes of nucleotide synthesis. It could be shown in vitro that DON treatment led to apoptosis, the programmed cell death. Different pathways were investigated. So it could be shown that the inner mitochondrial membrane was damaged,[13] and single strand DNA breaks were observed.[14] The exact mode of action remains unclear and needs further research.

DON is not approved as pharmaceutical agent, but is tested in combination with a recombinant glutaminase in clinical trials for the treatment of different solid tumors.[4]

References

  1. ↑ PubChem Databank
  2. 1 2 Dion HW, et al. (1954). "6-diazo-5-oxo-L-norleucine, A new tumor inhibitory substance. II: Isolation and Characterization". Antibiotics and Chemotherapy. 78: 3075–7.
  3. ↑ Yoshioka K, Takehara H, Okada A, Komi N (June 1992). "Glutamine antagonist with diet deficient in glutamine and aspartate reduce tumor growth". Tokushima J. Exp. Med. 39 (1–2): 69–76. PMID 1412455.
  4. 1 2 Mueller C, Al-Batran S, Jaeger E, Schmidt B, Bausch M, Unger C, Sethuraman N (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. 26 (May 20 Suppl): abstr 2533.
  5. ↑ DeWald HA and Moore AM: 6-Diazo-5-oxo-L-norleucine, a new tumor-inhibitory substance. Preparation of L (D and L)-forms, in Am. Chem. Soc. Meeting, Dallas, 1956, p. 13M .
  6. 1 2 3 4 5 6 7 8 9 Pinkus LM (1977). "Glutamine binding sites". Meth. Enzymol. Methods in Enzymology. 46: 414–27. doi:10.1016/S0076-6879(77)46049-X. ISBN 978-0-12-181946-0. PMID 909432.
  7. ↑ Ortlund E, Lacount MW, Lewinski K, Lebioda L (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. 39 (6): 1199–204. doi:10.1021/bi991797d. PMID 10684596.
  8. 1 2 Eidinoff ML, Knoll JE, Marano B, Cheong L (January 1957). "Pyrimidine Studies, I. Effect of DON (6-Diazo-5Oxo-L-Norleucine) on incorporation of precursors into nucleic acid pyrimidines" (PDF). 18 (1): 105–9.
  9. ↑ Levenberg B, Melnick I, Buchanan JM (1956). "Biosynthesis of the purines, XV. The effect of Aza-L-Serine and 6-Diazo-5-Oxo-L-Norleucine on inosinic acid biosynthesis de novo" (PDF). J Biol Chem. 225 (1): 163–176. PMID 13416227.
  10. 1 2 3 Ahluwalia GS, Grem JL, Hao Z, Cooney DA (1990). "Metabolism and action of amino acid analog anti-cancer agents". Pharmacol. Ther. 46 (2): 243–71. doi:10.1016/0163-7258(90)90094-I. PMID 2108451.
  11. ↑ Barclay RK, Phillipps MA (February 1966). "Effects of 6-diazo-5-oxol-norleucine and other tumor inhibitors on the biosynthesis of nicotinamide adenine dinucleotide in mice". Cancer Res. 26 (2): 282–6. PMID 4285554.
  12. ↑ Rosenbluth RJ, Cooney DA, Jayaram HN, Milman HA, Homan ER (August 1976). "DON, CONV and DONV-II. Inhibition of L-'asparagine synthetase in vivo". Biochem. Pharmacol. 25 (16): 1851–8. doi:10.1016/0006-2952(76)90189-1. PMID 9091.
  13. ↑ Wu F, Lukinius A, Bergström M, Eriksson B, Watanabe Y, Långström B (July 1999). "A mechanism behind the antitumour effect of 6-diazo-5-oxo-L-norleucine (DON): disruption of mitochondria". Eur. J. Cancer. 35 (7): 1155–61. doi:10.1016/S0959-8049(99)00099-4. PMID 10533463.
  14. ↑ Hiramoto K, Fujino T, Kikugawa K (June 1996). "DNA strand cleavage by tumor-inhibiting antibiotic 6-diazo-5-oxo-L-norleucine". Mutat. Res. 360 (2): 95–100. doi:10.1016/0165-1161(95)00073-9. PMID 8649470.
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