6-Diazo-5-oxo-L-norleucine: Difference between revisions
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{{DISPLAYTITLE:6-Diazo-5-oxo-<small>L</small>-norleucine}} |
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{{Drugbox |
{{Drugbox |
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| IUPAC_name = ( |
| IUPAC_name = <nowiki> (Z,5S)-5-Amino-1-diazonio-6-hydroxy-6-oxohex-1-en-2-olate >.<ref name="PubChem"> '' PubChem Databank [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5359375&loc=ec_rcs] </ref></nowiki> |
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| image = L-Diazooxonorleucine.svg|250px |
| image = L-Diazooxonorleucine.svg|250px |
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| CAS_number = 157-03-9 |
| CAS_number = 157-03-9 |
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| DrugBank = |
| DrugBank = |
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| C=6 | H=9 | N=3 |O=3 |
| chemical_formula = | C=6 | H=9 | N=3 |O=3 |
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| molecular_weight = 171.15 g/mol |
| molecular_weight = 171.15 g/mol |
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'''6-Diazo-5-oxo- |
'''6-Diazo-5-oxo-L-norleucine''' (DON) is a [[glutamine]] antagonist, which was isolated originally from [[Streptomyces]]. It is a non-standard [[amino acid]]. The [[diazo|diazo compound]] was characterized in 1956 by Henry W Dion et al.<ref name="Dion HW"> Dion HW et al. 6-diazo-5-oxo-L-norleucine, A new tumor inhibitory substance. II: Isolation and Characterization, Antibiotics and Chemotherapy, Vol 78, 1954, p. 3075-7''</ref>, who suggested a possible use in cancer therapy. This antitumoral efficacy was confirmed in different animal models.<ref name="Yoshioka"> '' Yoshioka K et al. [http://www.ncbi.nlm.nih.gov/pubmed/1412455?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=15 Glutamine antagonist with diet deficient in glutamine and aspartate reduce tumor growth], '' in Tokushima J Exp Med. 1992 Jun; 39 (1-2): 69-76'' </ref> 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]].<ref name="Mueller"> '' Mueller C et al. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=33084 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: 2008 (May 20 suppl; abstr 2533)'' </ref> |
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== Chemistry == |
== Chemistry == |
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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] |
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 274nm (E1%1cm. 683) and 244 nm (E1%1cm 376).<ref name="Dion HW"/> <ref name="DeWald"> '' 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 '' </ref> |
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== Biochemistry == |
== Biochemistry == |
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== Pharmacology == |
== Pharmacology == |
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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 |
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 <ref name="Wu"> '' Wu F et al. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T68-3WXNY3B-M&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=155dd51df48b9e39a3d45f0c046a471d A mechanism behind the antitumor effect of 6-diazo-5-oxo-L-norleucine (DON): disruption of mitochondria.], '' Eur J Cancer. 1999 Jul; 35(7):1155-61 '' </ref>, and single strand DNA breaks were observed<ref name="Hiramoto"> '' Hiramoto K et al. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B73H5-4K30SD9-4&_user=3864850&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1071162470&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=3864850&md5=ab2fad004d7b644151f6bed6e9f53b4f DNA strand cleavage by tumor-inhibiting antibiotic 6-diazo-5-oxo-L-norleucine], '' Mutat Res. 1996 Jun 10;360(2):95-100 '' </ref>. The exact mode of action remains unclear and needs further research. |
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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.<ref name="Mueller"/> |
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.<ref name="Mueller"/> |
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<references/> |
<references/> |
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{{DEFAULTSORT:Diazo-5-oxo-L-norleucine, 6-}} |
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[[Category:Chemotherapeutic agents]] |
[[Category:Chemotherapeutic agents]] |
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[[Category:amino acids]] |
[[Category:amino acids]] |
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Revision as of 11:17, 11 November 2009
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| Legal status |
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| Identifiers | |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.150.017 |
| Chemical and physical data | |
| Formula | C6H9N3O3 |
| Molar mass | 171.15 g/mol g·mol−1 |
6-Diazo-5-oxo-L-norleucine (DON) is a glutamine antagonist, which was isolated originally from Streptomyces. It is a non-standard amino acid. The diazo compound was characterized in 1956 by Henry W Dion et al.[1], who suggested a possible use in cancer therapy. This antitumoral efficacy was confirmed in different animal models.[2] 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.[3]
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 274nm (E1%1cm. 683) and 244 nm (E1%1cm 376).[1] [4]
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.[5] [6] In the following table gives a survey of DON targets.
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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 [12], and single strand DNA breaks were observed[13]. 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.[3]
References
- ^ a b Dion HW et al. 6-diazo-5-oxo-L-norleucine, A new tumor inhibitory substance. II: Isolation and Characterization, Antibiotics and Chemotherapy, Vol 78, 1954, p. 3075-7
- ^ Yoshioka K et al. Glutamine antagonist with diet deficient in glutamine and aspartate reduce tumor growth, in Tokushima J Exp Med. 1992 Jun; 39 (1-2): 69-76
- ^ a b Mueller C et al. 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: 2008 (May 20 suppl; abstr 2533)
- ^ 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
- ^ a b c d e f g h i Pinkus LM et al. Glutamine binding sites, Methods Enzymol, 1977, Vol. 46, 414–27
- ^ Ortlund E et al. [http://pubs.acs.org/doi/abs/10.1021/bi991797d 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 in Biochem (2000) 39: 1199-04
- ^ a b Eidinoff M et al. Pyrimidine Studies, I. Effect of DON (6-Diazo-5Oxo-L-Norleucine) on incorporation of precursors into nucleic acid pyrimidines” , 1957
- ^ Levenberg B et al. Biosynthesis of the purines, XV. The effect of Aza-L-Serine and 6-Diazo-5-Oxo-L-Norleucine on inosinic acid biosynthesis de novo ”, in J Biol Chem (1956): 163-176
- ^ a b c Ahluwalia GS et al. Metabolism and action of amino acid analog anti-cancer agents ”, in Pharmac. Ther. (1990) 46: 243-271
- ^ Barclay RK et al. Effects of 6-Diazo-5-Oxo-L-Norleucine and other tumor inhibitors on biosynthesis of nicotinamide adenine dinucleotide in mice ” , Cancer Research (1966) 26: 282-286 “
- ^ Rosenbluth RJ et al. DON, CONV and DONV-II. Inhibition of L-Asparagine Synthetase in Vivo ” , in Biochemical Pharmacology, Vol.25, 1851-1858 “
- ^ Wu F et al. A mechanism behind the antitumor effect of 6-diazo-5-oxo-L-norleucine (DON): disruption of mitochondria., Eur J Cancer. 1999 Jul; 35(7):1155-61
- ^ Hiramoto K et al. DNA strand cleavage by tumor-inhibiting antibiotic 6-diazo-5-oxo-L-norleucine, Mutat Res. 1996 Jun 10;360(2):95-100