Acyloxybutadiene tricarbonyl iron complexes as enzyme-triggered CO-releasing molecules (ET-CORMs): a structure–activity relationship study

Abstract

A series of η 4 -acyloxycyclohexadiene-Fe(CO) 3 complexes was prepared and fully characterized by spectroscopic methods including single crystal X-ray diffraction. For this purpose a new synthetic access to differently acylated 1,3-and 1,5-dienol-Fe(CO) 3 complexes was developed. The enzymatically triggered CO release from these compounds was monitored (detection of CO through GC and/or by means of a myoglobin assay) and the anti-inflammatory effect of the compounds was assessed by a cellular assay based on the inhibition of NO-production by inducible NO synthase (iNOS). It was demonstrated that the properties (rate of esterase-triggered CO release, iNOS inhibition, cytotoxicity) of the complexes strongly depend on the substitution pattern of the π-ligand and the nature of the acyloxy substituent.

Toward Carbon Monoxide–Based Therapeutics: Critical Drug Delivery and Developability Issues

“…79 Specifically, treatment of cells with compound 4 at 15 μM resulted in up to 68% suppression of LPS-induced NO formation relative to control cells, which were only treated with LPS. To improve the water solubility of ET-CO-RMs, cyclohexadienyl methyl phosphate iron tricarbonyl complex-based compound 5 was synthesized.…”

“…Using an enzyme to trigger CO release from CO-RMs is emerging as a promising strategy to address this issue. In 2011, Schmalz et al 79 developed acyloxybutadiene iron tricarbonyl complexes. This design takes advantage of the tight complexation of a diene with iron, which can bind and carry CO. Enzymatic cleavage of the ester group would lead to enol-ketone tautomerization and the conversion of the diene to an α, β-unsaturated ketone, which would lose affinity for Fe(II) and result in its oxidation to Fe(III) and the subsequent release of CO (Figure 2).…”

“…There are well-defined paths and criteria for addressing general developability issues in developing small molecule-based pharmaceuticals. 68, 79, 84, 85 One approach is to focus on small molecule CO-prodrugs. The chemistry of CO-release from a small organic molecule is not without precedents.…”

PhotoCORMs: CO release moves into the visible

“…Enzyme-triggered CORMs (ET-CORMs) make use of the presence of esterases in cells to bring about CO release at metal centres. [21][22][23][24] Triggering using small molecules is also possible, with the combination of a CORM with a second chemical agent [25][26][27] allowing temporal control of release. More exotic approaches have also been explored, for example release triggered by electromagnetic heating.…”

Live-Fibroblast IR Imaging of a Cytoprotective PhotoCORM Activated with Visible Light

“…To date the majority of CORMs are transition metal (TM) carbonyl complexes which under different stimuli are able to deliver CO to diseased or inflamed tissues in order to initiate and promote therapeutic effects at the site of disease. CO release in these molecules may be triggered by different strategies which include simple CO dissociation [4][5][6] , redox or ligand exchange mediated processes [7][8][9][10][11][12] , enzymatic triggering 13,14 or the use of electromagnetic radiation. [15][16][17] In general, at present, CORMs are not designed to target a specific receptor or intracellular target and their potential utility is credited to their fundamental ability to liberate CO.…”