| 词条 | 6-Diazo-5-oxo-L-norleucine | |||||||||||||||||||||||||||
| 释义 |
| Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 451225333 | IUPAC_name = (5S)-5-Amino-1-diazonio-6-hydroxy-6-oxohex-1-en-2-olate[1] | image = L-Diazooxonorleucine.svg | tradename = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = not approved{{where|date=February 2017}} | routes_of_administration = | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 157-03-9 | ATC_prefix = | ATC_suffix = | ATC_supplemental = | PubChem = 5359375 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | ChEBI = 138889 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 97485 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 16735775 | smiles = O=C(CC[C@H](N)C(O)=O)\\C=[N+]=[N-] | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 1S/C6H9N3O3/c7-5(6(11)12)2-1-4(10)3-9-8/h3,5H,1-2,7H2,(H,11,12)/t5-/m0/s1 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = YCWQAMGASJSUIP-YFKPBYRVSA-N | C=6 | H=9 | N=3 | O=3 | molecular_weight = 171.15 g/mol }}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] ChemistryDON 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] BiochemistryDON 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.[7][6] In the following table gives a survey of DON targets.
PharmacologyDON 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] References1. ^[https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5359375&loc=ec_rcs PubChem Databank] {{Glutamate metabolism and transport modulators}}{{DEFAULTSORT:Diazo-5-oxo-L-norleucine, 6-}}2. ^1 {{cite journal |vauthors =Dion HW |title=6-diazo-5-oxo-L-norleucine, A new tumor inhibitory substance. II: Isolation and Characterization |journal=Antibiotics and Chemotherapy |volume=78 |pages=3075–7 |year=1954|display-authors=etal}} 3. ^{{cite journal |vauthors =Yoshioka K, Takehara H, Okada A, Komi N |title=Glutamine antagonist with diet deficient in glutamine and aspartate reduce tumor growth |journal=Tokushima J. Exp. Med. |volume=39 |issue=1–2 |pages=69–76 |date=June 1992 |pmid=1412455 }} 4. ^1 {{cite journal |vauthors =Mueller C, Al-Batran S, Jaeger E, Schmidt B, Bausch M, Unger C, Sethuraman N |title=A phase IIa study of PEGylated glutaminase (PEG-PGA) plus 6-diazo-5-oxo-L-norleucine (DON) in patients with advanced refractory solid tumors |journal=J Clin Oncol |volume=26 |issue=May 20 Suppl |pages=abstr 2533 |year=2008 |url=http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=33084}} 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. ^{{cite journal |vauthors =Ortlund E, Lacount MW, Lewinski K, Lebioda L |title=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 |journal=Biochemistry |volume=39 |issue=6 |pages=1199–204 |date=February 2000 |pmid=10684596 |doi=10.1021/bi991797d }} 7. ^1 2 3 4 5 6 7 8 {{cite book |vauthors =Pinkus LM |title=Glutamine binding sites |journal=Meth. Enzymol. |volume=46 |pages=414–27 |year=1977 |pmid=909432 |doi=10.1016/S0076-6879(77)46049-X |series=Methods in Enzymology |isbn=978-0-12-181946-0 }} 8. ^1 {{cite journal |vauthors =Eidinoff ML, Knoll JE, Marano B, Cheong L |title=Pyrimidine Studies, I. Effect of DON (6-Diazo-5Oxo-L-Norleucine) on incorporation of precursors into nucleic acid pyrimidines |journal= |volume=18 |issue=1 |pages=105–9 |date=January 1957 |url=http://cancerres.aacrjournals.org/cgi/reprint/18/1/105.pdf}} 9. ^{{cite journal |vauthors =Levenberg B, Melnick I, Buchanan JM |title=Biosynthesis of the purines, XV. The effect of Aza-L-Serine and 6-Diazo-5-Oxo-L-Norleucine on inosinic acid biosynthesis de novo |journal=J Biol Chem |volume=225 |issue=1 |pages=163–176 |year=1956 |url=http://www.jbc.org/content/225/1/163.full.pdf |pmid=13416227}} 10. ^1 2 {{cite journal |vauthors =Ahluwalia GS, Grem JL, Hao Z, Cooney DA |title=Metabolism and action of amino acid analog anti-cancer agents |journal=Pharmacol. Ther. |volume=46 |issue=2 |pages=243–71 |year=1990 |pmid=2108451 |url=http://linkinghub.elsevier.com/retrieve/pii/0163-7258(90)90094-I |doi=10.1016/0163-7258(90)90094-I}} 11. ^{{cite journal |vauthors =Barclay RK, Phillipps MA |title=Effects of 6-diazo-5-oxol-norleucine and other tumor inhibitors on the biosynthesis of nicotinamide adenine dinucleotide in mice |journal=Cancer Res. |volume=26 |issue=2 |pages=282–6 |date=February 1966 |pmid=4285554 |url=http://cancerres.aacrjournals.org/cgi/reprint/26/2_Part_1/282}} 12. ^{{cite journal |vauthors =Rosenbluth RJ, Cooney DA, Jayaram HN, Milman HA, Homan ER |title=DON, CONV and DONV-II. Inhibition of L-'asparagine synthetase in vivo |journal=Biochem. Pharmacol. |volume=25 |issue=16 |pages=1851–8 |date=August 1976 |pmid=9091 |url=http://linkinghub.elsevier.com/retrieve/pii/0006-2952(76)90189-1 |doi=10.1016/0006-2952(76)90189-1}} 13. ^{{cite journal |vauthors =Wu F, Lukinius A, Bergström M, Eriksson B, Watanabe Y, Långström B |title=A mechanism behind the antitumour effect of 6-diazo-5-oxo-L-norleucine (DON): disruption of mitochondria |journal=Eur. J. Cancer |volume=35 |issue=7 |pages=1155–61 |date=July 1999 |pmid=10533463 |url=http://linkinghub.elsevier.com/retrieve/pii/S0959804999000994 |doi=10.1016/S0959-8049(99)00099-4}} 14. ^{{cite journal |vauthors =Hiramoto K, Fujino T, Kikugawa K |title=DNA strand cleavage by tumor-inhibiting antibiotic 6-diazo-5-oxo-L-norleucine |journal=Mutat. Res. |volume=360 |issue=2 |pages=95–100 |date=June 1996 |pmid=8649470 |doi=10.1016/0165-1161(95)00073-9}} 3 : Experimental cancer drugs|Amino acids|Diazo compounds |
|||||||||||||||||||||||||||
| 随便看 |
|
开放百科全书收录14589846条英语、德语、日语等多语种百科知识，基本涵盖了大多数领域的百科知识，是一部内容自由、开放的电子版国际百科全书。