Hemmersbach, Lars, Schreiner, Yannick, Zhang, Xinmiao, Dicke, Finn, Hunemeyer, Leon, Neudorfl, Jorg-Martin, Fleming, Thomas, Yard, Benito and Schmalz, Hans-Gunther (2022). Synthesis and Biological Evaluation of Water-Soluble Esterase-Activated CO-Releasing Molecules Targeting Mitochondria. Chem.-Eur. J., 28 (50). WEINHEIM: WILEY-V C H VERLAG GMBH. ISSN 1521-3765
Full text not available from this repository.Abstract
Due to the beneficial effects of carbon monoxide as a cell-protective and anti-inflammatory agent, CO-releasing molecules (CORMs) offer some promising potential applications in medicine. In this context, we synthesized a set of acyloxy-cyclohexadiene-Fe(CO)(3) complexes, all displaying a N-methyl-pyridinium triflate moiety in the ester side chain, as mitochondria-targeting esterase-triggered CORM prodrugs. Whereas the compounds in which the acyloxy substituent is attached to the 2-position of the diene-Fe(CO)(3) unit (A series) spontaneously release CO upon dissolution in phosphate buffer, which remarkably is partly suppressed in the presence of porcine liver esterase (PLE), the 1-substituted isomers (B series) show the expected PLE-induced release of CO (up to 3 equiv.). The biological activity of Mito-CORMs 2/3-B and their isophorone-derived analogs 2/3-A', which also displayed PLE-induced CO release, was assessed by using human umbilical vein endothelial cells (HUVEC). Whereas Mito-CORMs 2/3-B were not cytotoxic up to 500 mu M (MTT assay), Mito-CORMs 2/3-A' caused significant toxicity at concentrations above 50 mu M. The anti-inflammatory potential of both Mito-CORM variants was demonstrated by concentration-dependent down-regulation of the pro-inflammatory markers VCAM-1, ICAM-1 and CXCL1 as well as induction of HO-1 in TNF alpha-stimulated human umbilical vein endothelial cells (HUVECs; western blotting and qPCR). Energy phenotyping by seahorse real-time cell metabolic analysis, revealed opposing shifts of metabolic potentials in cells treated either with Mito-CORMs 2/3-B (increased mitochondrial respiration and glycolytic activity) or Mito-CORMs 2/3-A' (suppressed mitochondrial respiration and increased glycolytic activity). Thus, the Mito-CORMs represent valuable tools for the safe and targeted delivery of CO to mitochondria as a subcellular compartment to induce positive anti-inflammatory effects with only minor shifts in cellular energy metabolism. Also, due to their water solubility, these compounds provide a promising starting point for further pharmacological studies.
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||||||
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| URN: | urn:nbn:de:hbz:38-671858 | ||||||||||||||||||||||||||||||||||||||||
| DOI: | 10.1002/chem.202201670 | ||||||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Chem.-Eur. J. | ||||||||||||||||||||||||||||||||||||||||
| Volume: | 28 | ||||||||||||||||||||||||||||||||||||||||
| Number: | 50 | ||||||||||||||||||||||||||||||||||||||||
| Date: | 2022 | ||||||||||||||||||||||||||||||||||||||||
| Publisher: | WILEY-V C H VERLAG GMBH | ||||||||||||||||||||||||||||||||||||||||
| Place of Publication: | WEINHEIM | ||||||||||||||||||||||||||||||||||||||||
| ISSN: | 1521-3765 | ||||||||||||||||||||||||||||||||||||||||
| Language: | English | ||||||||||||||||||||||||||||||||||||||||
| Faculty: | Unspecified | ||||||||||||||||||||||||||||||||||||||||
| Divisions: | Unspecified | ||||||||||||||||||||||||||||||||||||||||
| Subjects: | no entry | ||||||||||||||||||||||||||||||||||||||||
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| URI: | http://kups.ub.uni-koeln.de/id/eprint/67185 |
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