Monensin

Structural formula
General
Non-proprietary name	Monensin
other names	Monensin A Rumensin (sodium salt) 2- [2-Ethyloctahydro-3'-methyl-5 '- [tetrahydro-6-hydroxy-6- (hydroxymethyl) -3,5-dimethyl-2 H -pyran-2-yl] - [2,2'- bifuran-5-yl]] - 9-hydroxy-β-methoxy-α, γ, 2,8-tetramethyl-1,6-dioxapsiro [4.5] decan-7-butanoic acid (2 S , 3 R , 4 S ) -4 - [(2 S , 5 R , 7 S , 8 R , 9 S ) -2 - [(2 R , 5 S ) -5-ethyl-5 - [( 2 R , 3 S , 5 R ) -5 - [(2 S , 3 S , 5 R , 6 R ) -6-hydroxy-6- (hydroxymethyl) -3,5-dimethyloxan-2-yl] -3- methyloxolan-2-yl] oxolan-2-yl] -7-hydroxy-2,8-dimethyl-1,10-dioxaspiro [4.5] decan-9-yl] -3-methoxy-2-methylpentanoic acid ( IUPAC )
Molecular formula	C 36 H 62 O 11
Brief description	white crystals (sodium salt) bitter odor
External identifiers / databases
CAS number 17090-79-8 22373-78-0 ( sodium salt ) EC number 241-154-0 ECHA InfoCard 100,037,398 PubChem 441145 ChemSpider 389937 Wikidata Q3493048
Drug information
ATC code	Q A16QA06 Q P51AH03
Drug class	Polyether antibiotics
Mechanism of action	Protein transport inhibition
properties
Molar mass	670.871 g mol −1
Melting point	103-105 ° C 267–269 ° C (sodium salt)
solubility	sparingly soluble in water (63 mg l −1 at 20 ° C) very soluble in organic solvents
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances danger H and P phrases H: 300 P: 264-301 + 310
Toxicological data	2–3 mg kg −1 ( LD 50 ,  horse ,  oral ) 12 mg kg −1 ( LD 50 ,  sheep ,  oral ) 17 mg kg −1 ( LD 50 ,  pigs ,  oral ) 20 mg kg −1 ( LD 50 ,  dog ,  oral ) 26 mg kg −1 ( LD 50 ,  goat ,  oral ) 35 mg kg −1 ( LD 50 ,  rat ,  oral ) 50–80 mg kg −1 ( LD 50 ,  cattle ,  oral ) 135 mg kg −1 ( LD 50 ,  mouse ,  oral ) 200 mg kg −1 ( LD 50 ,  chicken ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Monensin is an antibiotic substance from the group of polyether antibiotics and was isolated from the bacterium Streptomyces cinnamonensis . The mixture of substances consists largely of monensin A, in addition monensin B and C occur as accompanying substances.

The structure of monensin A was first identified in 1967 by Agtarap et al. and represents the first structure elucidation of a polyether antibiotic. The first total synthesis was achieved by Kishi et al. 1979. In 1980, W. Clark Still and colleagues published another total synthesis.

component	Molecular formula	Molar mass
Monensin A	C 36 H 62 O 11	670.87 g mol −1
Monensin B	C 35 H 60 O 11	656.84 g mol −1
Monensin C	C 37 H 64 O 11	684.90 g mol −1

Mechanism of action

The structure of the sodium complex of monensin A.

Monensin A is an ionophore related to the crown ethers with a tendency to complex with singly charged cations , such as Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Ag ⁺ and Tl ⁺ . It has the ability to transport these cations electronically through the lipid membrane of the cell and acts as an important Na + / H + antiporter . According to new research, it is possible that monensin transports sodium ions not only in an electroneutral way, but also in an electrogenic manner. This approach would not only explain the ionophore and associated antibacterial properties of the basic substance, but also those of the derivatives that do not have carboxy groups .

Monensin A and its derivatives block intra- and intercellular protein transport and thereby show antibiotic, antimalarial and other biological activities.

use

Monensin is used in the industrial animal production of poultry as a feed additive for the treatment of coccidiosis and histomoniasis . Its use in cattle fattening has been banned in the EU since 2006. In January 2013, Monensin was approved under the name Kexxtone for the prevention of the metabolic disorder ketosis in dairy cows in the peripartum phase.

Furthermore, monensin, like its derivatives monensin methyl ester and especially monensin decyl ester , is used in electrochemistry as an ion-selective electrode.

toxicology

Monensin shows ionophore activity in mammalian cells and is therefore toxic . This is particularly dangerous for horses , where the lethal dose is twenty-five times lower than that for ruminants. Poisoning of horses through inadvertent feeding of concentrated feed with monensin added to cows has led to deaths several times in the past. In most of the known cases, the contamination of the feed occurred with the simultaneous preparation of feed batches for cattle and horses in the same feed factory. This should therefore be avoided if possible. The death is a necrosis of cardiac muscle and a resulting cardiac arrest caused. Other symptoms include circulatory disorders with abnormal heart rates , tachycardia, and cardiac arrhythmias . Horses that survive the poisoning no longer show any abnormalities after two months.

Individual evidence

1. ^ ^{A b} G. WA Milne: Gardner's Commercially Important Chemicals: Definitions, Trade Names, and Properties . 1st edition. John Wiley & Sons , Hoboken 2005, ISBN 0-471-73661-9 , pp. 422 ( limited preview in Google Book search).
2. ↑ ^{a b c} data sheet Monensin sodium salt - 90–95% (TLC) from Sigma-Aldrich , accessed on May 8, 2016 ( PDF ).
3. ↑ ^{a b c d e f g h i j k} G. R. Doonan, CM Brown, TP Mullaney, DB Brooks, EG Ulmanis, and MR Slanker: Monensin poisoning in horses - an international incident . In: Canadian Veterinary Journal . 30, No. 2, February 1989, pp. 165-169. PMID 17423238 . PMC 1681029 (free full text).
4. ↑ ^{a b} Chemical Sampling Information - Monensin. USDL Occupational Safety and Health Administration , accessed May 9, 2016 . 
5. ^ M. Petrovic, S. Perez, D. Barcelo: Analysis, Removal, Effects and Risk of Pharmaceuticals in the Water Cycle: Occurrence and Transformation in the Environment . 2nd Edition. Elsevier, Amsterdam 2013, ISBN 0-444-62694-8 , pp. 458 ( limited preview in Google Book search).
6. ↑ D. Łowicki, A. Huczyński: Structure and Antimicrobial Properties of Monensin A and Its Derivatives: Summary of the Achievements . In: BioMed Research International . 2013, February 13, 2013. doi : 10.1155 / 2013/742149 . PMC 3586448 (free full text).
7. ↑ United States Pharmacopoeia (USP) 32 - National Formulary (NF) 27, p. 3001.
8. ↑ A. Agtarap, JW Chamberlin, M. Pinkerton, LK Steinrauf: Structure of monensic acid, a new biologically active compound . In: Journal of the American Chemical Society . 89, No. 22, October 1967, pp. 5737-5739. doi : 10.1021 / ja00998a062 .
9. ^ KC Nicolaou, EJ Sorensen: Classics in Total Synthesis: Targets, Strategies, Methods . VCH , Weinheim , Germany 1996, ISBN 3-527-29284-5 , pp. 185-187.
10. ↑ A. Huczyński, M. Ratajczak-Sitarz, A. Katrusiak, B. Brzezinski: Molecular structure of the 1: 1 inclusion complex of Monensin A lithium salt with acetonitrile . In: Journal of Molecular Structure . 871, No. 1-3, September, pp. 92-97. doi : 10.1016 / j.molstruc.2006.07.046 .
11. ↑ M. Pinkerton, LK Steinrauf: Molecular structure of monovalent metal cation complexes of monensin . In: Journal of Molecular Biology . 49, No. 3, May 14, 1970, pp. 533-546. doi : 10.1016 / 0022-2836 (70) 90279-2 .
12. ↑ A. Huczyński, J. Janczak, D. Łowicki, B. Brzezinski: Monensin A acid complexes as a model of electrogenic transport of sodium cation . In: Biochimica et Biophysica Acta - Biomembranes . 1818, September 2012, pp. 2108-2119. doi : 10.1016 / j.bbamem.2012.04.017 .
13. ^ HH Mollenhauer, DJ Morre, LD Rowe: Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity . In: Biochimica et Biophysica Acta - Biomembranes . 1031, No. 2, May 7, 1990, pp. 225-246. doi : 10.1016 / 0304-4157 (90) 90008-Z .
14. ↑ A. Huczyński, J. Stefańska, P. Przybylski, B. Brzezinski, F. Bartl: Synthesis and antimicrobial properties of Monensin A esters . In: Bioorganic & Medicinal Chemistry Letters . 18, No. 8, April 15, 2008, pp. 2585-2589. doi : 10.1016 / j.bmcl.2008.03.038 .
15. ↑ P. Butaye, LA Devriese, F. Haesebrouck: Antimicrobial Growth Promoters Used in Animal Feed: Effects of Less Well Known Antibiotics on Gram-Positive Bacteria . In: Clinical Microbiology Reviews . 16, No. 2, April 2003, pp. 175-188. doi : 10.1128 / CMR.16.2.175-188.2003 .
16. ↑ JIR Castanon: History of the Use of Antibiotic as Growth Promoters in European Poultry Feeds . In: Poultry Science . 86, No. 11, July 30, 2007, pp. 2466-2471. doi : 10.3382 / ps.2007-00249 .
17. ^ Committee for Medicinal Products for Veterinary Use: CVMP assessment report for Kexxtone (EMEA / V / C / 002235). European Medicines Agency, September 8, 2012, accessed May 10, 2016 . 
18. ↑ K. Tohda, K. Suzuki, N. Kosuge, H. Nagashima, K. Watanabe, H. Inoue, T. Shirai: A Sodium Ion Selective Electrode Based on a Highly Lipophilic Monensin Derivative and Its Application to the Measurement of Sodium Ion Concentrations in serum . In: Analytical Sciences . 6, No. 2, January 16, 1990, pp. 227-232. doi : 10.2116 / analsci.6.227 .
19. ↑ N. Kim, K. Park, I. Park, Y. Cho, Y. Bae: Application of a taste evaluation system to the monitoring of Kimchi fermentation . In: Biosensors and Bioelectronics . 20, No. 11, May 15, 2005, pp. 2283-2291. doi : 10.1016 / j.bios.2004.10.007 .
20. ↑ K. Toko: Sensor button . In: Sensors and Actuators B: Chemical . 64, No. 1-3, June 10, 2000, pp. 205-215. doi : 10.1016 / S0925-4005 (99) 00508-0 .