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 lipoxin A 4 analogue acyloxycyclohexadiene‐Fe(CO) 3 complex as esterase‐triggered CO‐releasing molecule (ET‐CORM). After adjustment the protecting group strategy, two such compounds were successfully prepared total synthesis (12 steps; 4–5 % overall yield) starting from deoxy‐ d ‐ribose exploiting Wittig olefination intermolecular Heck reaction key C−C bond‐forming steps. crucial late reduction aryl‐ketone moiety in presence highly sensitive dienol ester functionality was achieved with BH ‐SMe 2 catalytic amounts NaBH . Both target dose‐dependently toxic towards cultured human umbilical vein endothelial cells (HUVEC), LipET‐CORM 1‐A being slightly more toxic. While induction heme oxygenase 1 (HO‐1) HUVEC observed for both compounds, they did not inhibit TNF‐α‐mediated VCAM‐1 expression these cells. M2 polarized macrophages HO‐1 pronounced compared M1 macrophages. types downregulated lipopolysaccharide, but only rescued LipET‐CORM. 15‐Lipoxygenase (15‐LO) expressed influenced Collectively our data demonstrate that LipET‐CORMs induce The role intra‐cellular released resolution inflammation, however, remains be assessed.