Acivicin

Acivicin is an analog of glutamine. It is an inhibitor of gamma-glutamyl transferase.

Acivicin
Names
IUPAC name
(2S)-Amino[(5S)-3-chloro-4,5-dihydro-1,2-oxazol-5-yl]ethanoic acid
Other names
Antibiotic AT 125
Identifiers
CAS Number
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
PubChem CID
UNII
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 Y
    Key: QAWIHIJWNYOLBE-OKKQSCSOSA-N Y
  • 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
SMILES
  • Cl\C1=N\O[C@H]([C@@H](C(=O)O)N)C1
Properties
Chemical formula
C5H7ClN2O3
Molar mass 178.574
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

It is a fermentation product of Streptomyces sviceus.[1] It interferes with glutamate metabolism and inhibits glutamate dependent synthesis of enzymes, and is thereby potentially helpful in treatment of solid tumors.[2]

After its discovery in 1972, acivicin was studied as an anti-cancer agent, but trials were unsuccessful due to toxicity.[3]

Research

An in vitro study showed that Acivicin at a concentration of 5 μM Acivicin inhibited by 78% the growth of human pancreatic carcinoma cells (MIA PaCa-2) after 72 hours in continuous culture. It was also found that acivicin at a concentration of 450 μM irreversibly inactivated MIA PaCa-2 γ-glutamyl transpeptidase (10 nmol/min/106 cells) with an inactivation half-life of 80 minutes.[1]

Phase I studies

Phase I dose escalating studies conducted in 23 cancer patients administered acivicin with a concomitant 96-h i.v. infusion of a mixture of 16 amino acids showed reversible, dose-limiting CNS toxicity, characterized by lethargy, confusion and decreased mental status.

References

  1. Allen, L.; Meck, R.; Yunis, A. (1980). "The Inhibition of γ-Glutamyl Transpeptidase from Human Pancreatic Carcinoma Cells by (αS,5S)-α-Amino-3-chloro-4,5-dihydro-5-isoxazoleacetic Acid (AT-125; NSC-163501)". Research Communications in Chemical Pathology and Pharmacology. 27 (1): 175–182. PMID 6102405.
  2. Hidalgo, M.; Rodriguez, G.; Kuhn, J. G.; Brown, T.; Weiss, G.; MacGovren, J. P.; von Hoff, D. D.; Rowinsky, E. K. (1998). "A Phase I and Pharmacological Study of the Glutamine Antagonist Acivicin with the Amino Acid Solution Aminosyn in Patients with Advanced Solid Malignancies". Clinical Cancer Research. 4 (11): 2763–2770. PMID 9829740.
  3. Kreuzer, Johannes; Bach, Nina C.; Forler, Daniel; Sieber, Stephan A. (2015). "Target discovery of acivicin in cancer cells elucidates its mechanism of growth inhibition". Chemical Science. 6 (1): 237–245. doi:10.1039/C4SC02339K. PMC 4285139. PMID 25580214.


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