Metabolites-BOC Sciences

Acivicin - CAS 42228-92-2

Catalog number: BBF-00541

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Catalog Number BBF-00541
CAS 42228-92-2
Description Acivicin is an isoxazole antibiotic isolated from Streptomyces. sviceus. Acivicin is a glutamine analog that irreversibly inhibits glutamine-dependent amidotransferases involved in nucleotide and amino acid biosynthesis (Kis = 10 and 560 μM for anthranilate synthase and glutamate synthase, respectively) as a potent antitumor antibiotic that induces apoptosis in human lymphoblastoid cells. Acivicin is an inhibitor of GGT used for solid tumor research
Molecular Formula C5H7ClN2O3
Molecular Weight 178.57
Synonyms (S-(R*,R*))-4,5-Dihydro-alpha-amino-3-chloro-5-isoxazoleacetic acid; (alpha-S,5S)-alpha-Amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid; (alphaS,5S)-alpha-Amino-3-chlor-4,5-dihydro-5-isoxazolylessigsaeure
IUPAC Name (2S)-2-amino-2-[(5S)-3-chloro-4,5-dihydro-1,2-oxazol-5-yl]acetic acid
Canonical SMILES C1C(ON=C1Cl)C(C(=O)O)N
InChI InChI=1S/C5H7ClN2O3/c6-3-1-2(11-8-3)4(7)5(9)10/h2,4H,1,7H2,(H,9,10)/t2-,4-/m0/s1
Boiling Point 341.6°C at 760 mmHg
Melting Point 228-230 °C
Purity ≥98% by HPLC
Density 1.85 g/cm3
Solubility Soluble in DMSO
Appearance White to Beige Powder
Application Protease inhibitor
Shelf Life As supplied, 2 years from the QC date provided on the Certificate of Analysis, when stored properly.
Storage Store at -20°C
1.Target discovery of acivicin in cancer cells elucidates its mechanism of growth inhibition†Electronic supplementary information (ESI) available: Synthesis, cloning, protein expression, purification
Kreuzer J1, Bach NC1, Forler D2, Sieber SA1. Chem Sci. 2014 Dec 1;6(1):237-245. Epub 2014 Sep 26.
Acivicin is a natural product with diverse biological activities. Several decades ago its clinical application in cancer treatment was explored but failed due to unacceptable toxicity. The causes behind the desired and undesired biological effects have never been elucidated and only limited information about acivicin-specific targets is available. In order to elucidate the target spectrum of acivicin in more detail we prepared functionalized derivatives and applied them for activity based proteomic profiling (ABPP) in intact cancer cells. Target deconvolution by quantitative mass spectrometry (MS) revealed a preference for specific aldehyde dehydrogenases. Further in depth target validation confirmed that acivicin inhibits ALDH4A1 activity by binding to the catalytic site. In accordance with this, downregulation of ALDH4A1 by siRNA resulted in a severe inhibition of cell growth and might thus provide an explanation for the cytotoxic effects of acivicin.
2.Inhibiting lung lining fluid glutathione metabolism with GGsTop as a novel treatment for asthma.
Tuzova M1, Jean JC1, Hughey RP2, Brown LA3, Cruikshank WW1, Hiratake J4, Joyce-Brady M1. Front Pharmacol. 2014 Jul 31;5:179. doi: 10.3389/fphar.2014.00179. eCollection 2014.
Asthma is characterized by airway inflammation. Inflammation is associated with oxidant stress. Airway epithelial cells are shielded from this stress by a thin layer of lung lining fluid (LLF) which contains an abundance of the antioxidant glutathione. LLF glutathione metabolism is regulated by γ-glutamyl transferase (GGT). Loss of LLF GGT activity in the mutant GGT(enu1) mouse causes an increase in baseline LLF glutathione content which is magnified in an IL-13 model of allergic airway inflammation and protective against asthma. Normal mice are susceptible to asthma in this model but can be protected with acivicin, a GGT inhibitor. GGT is a target to treat asthma but acivicin toxicity limits clinical use. GGsTop is a novel GGT inhibitor. GGsTop inhibits LLF GGT activity only when delivered through the airway. In the IL-13 model, mice treated with IL-13 and GGsTop exhibit a lung inflammatory response similar to that of mice treated with IL-13 alone.
3.Structure of Bacillus subtilis γ-glutamyltranspeptidase in complex with acivicin: diversity of the binding mode of a classical and electrophilic active-site-directed glutamate analogue.
Ida T1, Suzuki H2, Fukuyama K1, Hiratake J3, Wada K4. Acta Crystallogr D Biol Crystallogr. 2014 Feb;70(Pt 2):607-14. doi: 10.1107/S1399004713031222. Epub 2014 Jan 31.
γ-Glutamyltranspeptidase (GGT) is an enzyme that plays a central role in glutathione metabolism, and acivicin is a classical inhibitor of GGT. Here, the structure of acivicin bound to Bacillus subtilis GGT determined by X-ray crystallography to 1.8 Å resolution is presented, in which it binds to the active site in a similar manner to that in Helicobacter pylori GGT, but in a different binding mode to that in Escherichia coli GGT. In B. subtilis GGT, acivicin is bound covalently through its C3 atom with sp2 hybridization to Thr403 Oγ, the catalytic nucleophile of the enzyme. The results show that acivicin-binding sites are common, but the binding manners and orientations of its five-membered dihydroisoxazole ring are diverse in the binding pockets of GGTs.
4.Monitoring γ-glutamyl transpeptidase activity and evaluating its inhibitors by a water-soluble near-infrared fluorescent probe.
Li L1, Shi W2, Wu X1, Gong Q1, Li X1, Ma H1. Biosens Bioelectron. 2016 Jul 15;81:395-400. doi: 10.1016/j.bios.2016.03.021. Epub 2016 Mar 12.
The first near-infrared fluorescent probe with excellent water-solubility for γ-glutamyl transpeptidase (GGT) has been developed by combining glutathione (GSH) as a recognition unit with a near-infrared hemicyanine fluorophore through an acrylyl linker. The probe exhibits a highly selective and sensitive fluorescent off-on response to GGT with a detection limit of 0.50U/L, and the response mechanism is based on the enzyme-catalyzed cleavage of the γ-glutamyl bond of GSH, followed by the spontaneous intramolecular cyclization and the release of the fluorophore. Notably, the probe has been used to image GGT in zebrafish and evaluate the inhibition ability of three common inhibitors of GGT both in vitro and in vivo, revealing that their inhibition efficiencies are acivicin >6-diazo-5-oxo-L-norleucine >L-serine-borate complex, and their corresponding IC50 values are 0.11±0.01mM, 0.34±0.04mM and 2.06±0.24mM, respectively. The proposed probe is simple, and may have great potential for screening GGT inhibitors.
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