Synthesis and biological evaluation of water-soluble esterase-activated CO-releasing molecules targeting mitochondria

• Verfasst von: Hemmersbach, Lars [VerfasserIn]
• Verfasst von: Schreiner, Yannick [VerfasserIn]
• Verfasst von: Zhang, Xinmiao [VerfasserIn]
• Verfasst von: Dicke, Finn [VerfasserIn]
• Verfasst von: Hünemeyer, Leon [VerfasserIn]
• Verfasst von: Neudörfl, Jörg-Martin [VerfasserIn]
• Verfasst von: Fleming, Thomas [VerfasserIn]
• Verfasst von: Yard, Benito A. [VerfasserIn]
• Verfasst von: Schmalz, Hans-Günther [VerfasserIn]
• Titel: Synthesis and biological evaluation of water-soluble esterase-activated CO-releasing molecules targeting mitochondria
• Verf.angabe: Lars Hemmersbach, Yannick Schreiner, Xinmiao Zhang, Finn Dicke, Leon Hünemeyer, Jörg-Martin Neudörfl, Thomas Fleming, Benito Yard, and Hans-Günther Schmalz
• E-Jahr: 2022
• Jahr: September 6, 2022
• Umfang: 9 S.
• Fussnoten: Online veröffentlicht: 30. Juni 2022 ; Gesehen am 25.09.2023
• Titel Quelle: Enthalten in: Chemistry - a European journal
• Ort Quelle: Weinheim : Wiley-VCH, 1995
• Jahr Quelle: 2022
• Band/Heft Quelle: 28(2022), 50 vom: Sept., Artikel-ID 202201670, Seite 1-9
• ISSN Quelle: 1521-3765
• DOI: doi:10.1002/chem.202201670
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: carbon monoxide
• Sach-SW: esterases
• Sach-SW: inflammation
• Sach-SW: iron carbonyl complexes
• Sach-SW: prodrugs
• K10plus-PPN: 1860231276

Abstract

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??M (MTT assay), Mito-CORMs 2/3-A? caused significant toxicity at concentrations above 50??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 TNFα-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.