Acivicin

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	42228-92-2 ;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:74545 ;
ChEMBL	ChEMBL1231101 ;
ChemSpider	259938 ;
PubChem CID	294641;
UNII	O0X60K76I6 ;
CompTox Dashboard (EPA)	DTXSID0046010 ;
	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 Key: QAWIHIJWNYOLBE-OKKQSCSOSA-N ; 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).
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	Infobox references

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

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 2 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.
↑ 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.
↑ 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.

External links

Obrador, E.; Carretero, J.; Ortega, A.; Medina, I.; Rodilla, V.; Pellicer, J. A.; Estrela, J. M. (2002). "γ-Glutamyl Transpeptidase Overexpression Increases Metastatic Growth of B16 Melanoma Cells in the Mouse Liver". Hepatology. 35 (1): 74–81. doi:10.1053/jhep.2002.30277. PMID 11786961.
Schmees, C.; Prinz, C.; Treptau, T.; Rad, R.; Hengst, L.; Voland, P.; Bauer, S.; Brenner, L.; Schmid, R. M.; Gerhard, M. (2007). "Inhibition of T-Cell Proliferation by Helicobacter pylori γ-Glutamyl Transpeptidase". Gastroenterology. 132 (5): 1820–1833. doi:10.1053/j.gastro.2007.02.031. PMID 17484877.

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[Allen-1] 1 2 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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