Synthesis of bifunctional Lipoxin-derived Enzyme-Triggered CO-Releasing Molecules (LipET-CORMs)
Abstract In an attempt to develop new anti-inflammatory agents which act by co-release of carbon monoxide (CO) and a specialized pro-resolving mediator, we designed conjugates of a lipoxin A4 analogue and an acyloxycyclohexadiene-Fe(CO)3 complex as an esterase-triggered CO-releasing molecule (ET-COR...
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| Main Authors: | , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 1, 2023
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| In: |
European journal of organic chemistry
Year: 2023, Volume: 26, Issue: 9, Pages: 1-6 |
| ISSN: | 1099-0690 |
| DOI: | 10.1002/ejoc.202201424 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1002/ejoc.202201424 Verlag, kostenfrei, Volltext: https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejoc.202201424 
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| Author Notes: | Lars Hemmersbach, Ruth Adam, Christina Plevnali, Xinmiao Zhang, Benito Yard, Hans-Günther Schmalz |
| Summary: | Abstract In an attempt to develop new anti-inflammatory agents which act by co-release of carbon monoxide (CO) and a specialized pro-resolving mediator, we designed conjugates of a lipoxin A4 analogue and an acyloxycyclohexadiene-Fe(CO)3 complex as an esterase-triggered CO-releasing molecule (ET-CORM). After adjustment of the protecting group strategy, two of such compounds were successfully prepared by total synthesis (12 steps; 4?5?% overall yield) starting from deoxy-d-ribose and exploiting a Wittig olefination and an intermolecular Heck reaction as key C?C bond-forming steps. A crucial late reduction of an aryl-ketone moiety in the presence of a highly sensitive dienol ester functionality was achieved with BH3-SMe2 in the presence of catalytic amounts of NaBH4. Both target compounds were dose-dependently toxic towards cultured human umbilical vein endothelial cells (HUVEC), with LipET-CORM 1-A being slightly more toxic. While induction of heme oxygenase 1 (HO-1) in HUVEC was observed for both compounds, they did not inhibit TNF-α-mediated VCAM-1 expression in these cells. In M2 polarized macrophages HO-1 expression was more pronounced as compared to M1 polarized macrophages. In both types of macrophages HO-1 expression was downregulated by lipopolysaccharide, but only in M2 macrophages HO-1 expression was rescued by LipET-CORM. 15-Lipoxygenase (15-LO) was only expressed in M2 macrophages and was not influenced by LipET-CORM. Collectively our data demonstrate that LipET-CORMs induce HO-1 expression in endothelial cells and M2 polarized macrophages. The role of the intra-cellular released lipoxin A4 in resolution of inflammation, however, remains to be assessed. |
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| Item Description: | Online veröffentlicht: 20. Januar 2023 Gesehen am 04.09.2024 |
| Physical Description: | Online Resource |
| ISSN: | 1099-0690 |
| DOI: | 10.1002/ejoc.202201424 |