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Chemistry. 2015 Oct 12;21(42):14708-12. doi: 10.1002/chem.201502474. Epub 2015 Aug 28.

An N-Acetyl Cysteine Ruthenium Tricarbonyl Conjugate Enables Simultaneous Release of CO and Ablation of Reactive Oxygen Species.

Author information

1
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa (Portugal) www.gbernardes-lab.com.
2
Instituto de Tecnologia Química e Biológica-António Xavier, Universidade Nova de Lisboa, Av da República, 2780-157 Oeiras (Portugal).
3
Alfama Ltd., Instituto de Biologia Experimental e Tecnológica, IBET, Av. da República, EAN, 2780-157 Oeiras (Portugal).
4
Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge (UK).
5
School of Pharmaceutical Sciences, University of Cartagena, Campus of Zaragocilla, Cartagena, Bolivar 130015 (Colombia).
6
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa (Portugal) www.gbernardes-lab.com. gbernardes@medicina.ulisboa.pt, gb453@cam.ac.uk.
7
Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge (UK). gbernardes@medicina.ulisboa.pt, gb453@cam.ac.uk.

Abstract

We have designed and synthesised a [Ru(CO)3 Cl2 (NAC)] pro-drug that features an N-acetyl cysteine (NAC) ligand. This NAC carbon monoxide releasing molecule (CORM) conjugate is able to simultaneously release biologically active CO and to ablate the concurrent formation of reactive oxygen species (ROS). Complexes of the general formulae [Ru(CO)3 (L)3 ](2+) , including [Ru(CO)3 Cl(glycinate)] (CORM-3), have been shown to produce ROS through a water-gas shift reaction, which contributes significantly, for example, to their antibacterial activity. In contrast, NAC-CORM conjugates do not produce ROS or possess antibacterial activity. In addition, we demonstrate the synergistic effect of CO and NAC both for the inhibition of nitric oxide (formation) and in the expression of tumour-necrosis factor (TNF)-α. This work highlights the advantages of combining a CO-releasing scaffold with the anti-oxidant and anti-inflammatory drug NAC in a unique pro-drug.

KEYWORDS:

N-acetyl cysteine; anti-oxidants; carbon monoxide; prodrugs; reactive oxygen species; ruthenium

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