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Redox Biology 2 (2014) 739Contents lists readily available at ScienceDirectRedox Biologyjournal homepage: elsevier.com/locate/redoxResearch PaperDifferent design of enzyme-triggered CO-releasing molecules (ET-CORMs) reveals quantitative variations in biological activities with regards to toxicity and inflammationE. Stamellou a,b,1,n, D. Storz b,1, S. Botov c, E. Ntasis b, J. Wedel b, S. Sollazzo c, B.K. Kr er b, W. van Son d, M. Seelen d, H.G. Schmalz c, A. Schmidt c, M. Hafner a, B.A. Yard baInstitute for Molecular and Cellular Biology, Mannheim University of Applied Sciences, Mannheim, Germany Vth. Health-related Department, Health-related Faculty Mannheim, Ruprecht Karls University, Heidelberg Mannheim, Germany Department of Chemistry, University of Cologne, Cologne, Germany d Division of Nephrology, Academic Medical Center, Groningen, The Netherlandsb cart ic l e i nf oArticle history: Received 7 Might 2014 Received in revised form 29 Could 2014 Accepted two June 2014 Available online 5 June 2014 Key phrases: Endothelial cells Carbon monoxide Adhesion molecules Enzyme-triggered CORMsa b s t r a c tAcyloxydiene e(CO)three complexes can act as enzyme-triggered CO-releasing molecules (ET-CORMs). Their biological activity strongly is dependent upon the mother compound from which they are derived, i.e. cyclohexenone or cyclohexanedione, and on the position of your ester functionality they harbour. The present study P2X1 Receptor medchemexpress addresses if the latter characteristic affects CO release, if cytotoxicity of ET-CORMs is mediated by means of iron release or inhibition of cell respiration and to what extent cyclohexenone and cyclohexanedione derived ET-CORMs differ in their ability to counteract TNF- mediated inflammation. Irrespective of the formulation (DMSO or cyclodextrin), toxicity in HUVEC was drastically larger for ET-CORMs bearing the ester functionality in the outer (rac-4), as when compared with the inner (rac-1) position with the cyclohexenone moiety. This was paralleled by an enhanced CO release in the former ET-CORM. Toxicity was not mediated by way of iron as EC50 values for rac-4 have been drastically lower than for FeCl2 or FeCl3 and have been not influenced by iron chelation. ATP depletion preceded toxicity suggesting impaired cell respiration as putative bring about for cell death. In long-term HUVEC cultures inhibition of VCAM-1 expression by rac-1 waned in time, when for the cyclohexanedione derived rac-8 inhibition seems to raise. NFB was inhibited by both rac-1 and rac-8 independent of IB degradation. Both ET-CORMs activated Nrf-2 and consequently induced the expression of HO-1. This study further delivers a rational framework for designing acyloxydiene e(CO)3 complexes as ET-CORMs with differential CO release and biological activities. We also provide a improved understanding of how these complexes affect cell-biology in mechanistic terms. 2014 The Authors. Published by Elsevier B.V. This really is an open access short article beneath the CC BY-NC-ND licens.