Synthesis of bifunctional Lipoxin-derived Enzyme-Triggered CO-Releasing Molecules (LipET-CORMs)

• Verfasst von: Hemmersbach, Lars [VerfasserIn]
• Verfasst von: Adam, Ruth [VerfasserIn]
• Verfasst von: Plevnali, Christina [VerfasserIn]
• Verfasst von: Zhang, Xinmiao [VerfasserIn]
• Verfasst von: Yard, Benito A. [VerfasserIn]
• Verfasst von: Schmalz, Hans-Günther [VerfasserIn]
• Titel: Synthesis of bifunctional Lipoxin-derived Enzyme-Triggered CO-Releasing Molecules (LipET-CORMs)
• Verf.angabe: Lars Hemmersbach, Ruth Adam, Christina Plevnali, Xinmiao Zhang, Benito Yard, Hans-Günther Schmalz
• E-Jahr: 2023
• Jahr: March 1, 2023
• Umfang: 6 S.
• Illustrationen: Illustrationen
• Fussnoten: Online veröffentlicht: 20. Januar 2023 ; Gesehen am 04.09.2024
• Titel Quelle: Enthalten in: European journal of organic chemistry
• Ort Quelle: Weinheim : Wiley-VCH Verl., 1998
• Jahr Quelle: 2023
• Band/Heft Quelle: 26(2023), 9, Artikel-ID e202201424, Seite 1-6
• ISSN Quelle: 1099-0690
• DOI: doi:10.1002/ejoc.202201424
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: carbon monoxide
• Sach-SW: inflammation
• Sach-SW: iron carbonyl complexes
• Sach-SW: lipoxins
• Sach-SW: prodrugs
• K10plus-PPN: 1901850366

Abstract

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.