Synthesis and Performance of Acyloxy-diene-Fe(CO)₃ Complexes with Variable Chain Lengths as Enzyme-Triggered Carbon Monoxide-Releasing Molecules

Abstract

Novel η4-acyloxy-cyclohexadiene-Fe(CO)3 complexes (with variable length of the acyloxy chain) were synthesized as potential enzyme-triggered carbon monoxide (CO)-releasing molecules (ET-CORMs). The molecular structure of two complexes was additionally confirmed by X-ray crystallography. The enzyme-triggered CO-releasing activity of the compounds was assessed under physiological conditions (37 °C, 0.1 M phosphate buffer, pH = 7.4) by headspace gas chromatography (GC) and additionally by means of a myoglobin assay (UV). The relative rate of CO release and the amount of liberated CO were found to depend on the length of the acyloxy chain and its position at the diene unit (outer or inner position). Some of the new ET-CORMs exhibited very good biological activity as assessed in different cellular assays (cytotoxicity, protective effect against hypothermia-associated cell damage, and inhibition of TNF-α-mediated VCAM-1 expression).

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

“…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). 80 These enzyme-triggered CO-RMs (ET-CO-RMs) ( 1 and 2 ) are stable under physiological conditions. The biological effects of these ET-CO-RMs are related to both the organic components and the rate of CO release.…”

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.…”

Design of biomaterials for intracellular delivery of carbon monoxide

“…[46][47][48][49][50][51][52] This concept is based on enzymatic reactions of intracellular enzymes with ligands of CORMs designed as esterase-reactive moieties. The first examples of ET-CORMs were acyloxybutadiene-Fe(CO) 3 complexes.…”

“…5b). Several versions of ET-CORMs have been reported with alterations provided by modifying the substitution pattern 47 and racemic structures, 48 to tune the kinetics of the CO-release reaction and the amounts of CO released (Fig. 5c).…”

“…5c). 48 A phosphoryloxy-Fe(CO) 3 complex (7) has been reported as a water-soluble and phosphatase reactive CORM. 49 The effects of these ET-CORMs have been investigated by evaluating their influence on cell viability and activity of inducible NO synthase (iNOS).…”