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In this context, we synthesized a set of acyloxy\u2010cyclohexadiene\u2010Fe(CO)<jats:sub>3<\/jats:sub> complexes, all displaying a <jats:italic>N<\/jats:italic>\u2010methyl\u2010pyridinium triflate moiety in the ester side chain, as mitochondria\u2010targeting esterase\u2010triggered CORM prodrugs. Whereas the compounds in which the acyloxy substituent is attached to the 2\u2010position of the diene\u2010Fe(CO)<jats:sub>3<\/jats:sub> 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\u2010substituted isomers (B series) show the expected PLE\u2010induced release of CO (up to 3\u2005equiv.). The biological activity of Mito\u2010CORMs <jats:bold>2<\/jats:bold>\/<jats:bold>3<\/jats:bold>\u2010<jats:bold>B<\/jats:bold> and their isophorone\u2010derived analogs <jats:bold>2\/3<\/jats:bold>\u2010<jats:bold>A<\/jats:bold>\u2019, which also displayed PLE\u2010induced CO release, was assessed by using human umbilical vein endothelial cells (HUVEC). Whereas Mito\u2010CORMs <jats:bold>2\/3<\/jats:bold>\u2010<jats:bold>B<\/jats:bold> were not cytotoxic up to 500\u2005\u03bcM (MTT assay), Mito\u2010CORMs <jats:bold>2<\/jats:bold>\/<jats:bold>3<\/jats:bold>\u2010<jats:bold>A<\/jats:bold>\u2019 caused significant toxicity at concentrations above 50\u2005\u03bcM. The anti\u2010inflammatory potential of both Mito\u2010CORM variants was demonstrated by concentration\u2010dependent down\u2010regulation of the pro\u2010inflammatory markers VCAM\u20101, ICAM\u20101 and CXCL1 as well as induction of HO\u20101 in TNF\u03b1\u2010stimulated human umbilical vein endothelial cells (HUVECs; western blotting and qPCR). Energy phenotyping by seahorse real\u2010time cell metabolic analysis, revealed opposing shifts of metabolic potentials in cells treated either with Mito\u2010CORMs <jats:bold>2\/3<\/jats:bold>\u2010<jats:bold>B<\/jats:bold> (increased mitochondrial respiration and glycolytic activity) or Mito\u2010CORMs <jats:bold>2\/3<\/jats:bold>\u2010<jats:bold>A<\/jats:bold>\u2019 (suppressed mitochondrial respiration and increased glycolytic activity). Thus, the Mito\u2010CORMs represent valuable tools for the safe and targeted delivery of CO to mitochondria as a subcellular compartment to induce positive anti\u2010inflammatory 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.<\/jats:p>","DOI":"10.1002\/chem.202201670","type":"journal-article","created":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T09:39:18Z","timestamp":1656581958000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Synthesis and Biological Evaluation of Water\u2010Soluble Esterase\u2010Activated CO\u2010Releasing Molecules Targeting Mitochondria"],"prefix":"10.1002","volume":"28","author":[{"given":"Lars","family":"Hemmersbach","sequence":"first","affiliation":[{"name":"Department of Chemistry Universit\u00e4t zu K\u00f6ln  Greinstrasse 4 50939 K\u00f6ln Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yannick","family":"Schreiner","sequence":"additional","affiliation":[{"name":"Vth Medical Department Medical Faculty Mannheim University of Heidelberg  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