title: Enzyme-triggered CO-releasing molecules (ET-CORMs): evaluation of biological activity in relation to their structure.
abstract: Acyloxydiene-Fe(CO)3 complexes act as enzyme-triggered CO-releasing molecules (ET-CORMs) and can deliver CO intracellularly via esterase-mediated hydrolysis. The protective properties of structurally different ET-CORMs on hypothermic preservation damage and their ability to inhibit VCAM-1 expression were tested on cultured human umbilical vein endothelial cells (HUVEC) and renal proximal tubular epithelial cells (PTEC) using a structure-activity approach. Cytotoxicity of ET-CORMs, protection against hypothermic preservation damage, and inhibition of VCAM-1 expression were assessed. Cytotoxicity of 2-cyclohexenone and 1,3-cyclohexanedione-derived ET-CORMs was more pronounced in HUVEC compared to PTEC and was dependent on the position and type of the ester (acyloxy) substituent(s) (acetate>pivalate>palmitate). Protection against hypothermic preservation injury was only observed for 2-cyclohexenone-derived ET-CORMs and was not mediated by the ET-CORM decomposition product 2-cyclohexenone itself. Structural requirements for protection by these ET-CORMs were different for HUVEC and PTEC. Protection was affected by the nature of the ester functionality in both cell lines. VCAM-1 expression was inhibited by both 2-cyclohexenone- and 1,3-cyclohexanedione-derived ET-CORMs. 2-Cyclohexenone, but not 1,3-cyclohexanedione, also inhibited VCAM-1 expression. We demonstrate that structural alterations of ET-CORMs significantly affect their biological activity. Our data also indicate that different ET-CORMs behave differently in various cell types (epithelial vs endothelial). These findings warrant further studies not only to elucidate the structure-activity relation of ET-CORMs in mechanistic terms but also to assess if structural optimization will yield ET-CORMs with restricted cell specificity.
authors.affiliation: Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Romanski
authors.affiliation: Vth Medical Department, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. Electronic address: stamellou.eleni@googlemail.com.
authors.forename: E
authors.initials: E
authors.lastname: Stamellou
authors.affiliation: Vth Medical Department, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
authors.forename: J T
authors.initials: JT
authors.lastname: Jaraba
authors.affiliation: Vth Medical Department, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Storz
authors.affiliation: Vth Medical Department, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
authors.forename: B K
authors.initials: BK
authors.lastname: Krämer
authors.affiliation: Institut für Molekülar- and Zellbiologie, Hochschule Mannheim, Paul-Wittsack-Str. 10, 68163 Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hafner
authors.affiliation: Institut für Organische Chemie, Universität Regensburg, Universitätsstrasse 31, 93053 Regensburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Amslinger
authors.affiliation: Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany.
authors.forename: H G
authors.initials: HG
authors.lastname: Schmalz
authors.affiliation: Vth Medical Department, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
authors.forename: B A
authors.initials: BA
authors.lastname: Yard
mesh_terms: D015153:Blotting, Western; D002070:Butadienes / Q000737:chemistry* / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000008:administration & dosage*; D019610:Cytoprotection; D006801:Humans; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D002070:Butadienes; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D002248:Carbon Monoxide
keywords: Adhesion molecules; Carbon monoxide; Endothelial cells; HUVEC; Inflammation; PTEC; human umbilical vein endothelial cells; proximal tubular epithelial cells.