Bioactive Properties of Iron-Containing Carbon Monoxide-Releasing Molecules

Abstract

Carbon monoxide-releasing molecules (CO-RMs) are compounds capable of delivering controlled amounts of CO within a cellular environment. Ruthenium-based carbonyls [tricarbonyldichloro ruthenium(II) dimer and tricarbonylchloro-(glycinato)ruthenium(II)] and boronacorbonates (sodium boranocarbonate) have been shown to promote vasodilatory, cardioprotective, and anti-inflammatory activities in a variety of experimental models. Here, we extend our previous studies by showing that -4-(4-bromo-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F3), an irontricarbonyl complex that contains a 2-pyrone motif, liberates CO in vitro and exerts pharmacological actions that are typical of CO gas. Specifically, CORM-F3 caused vasorelaxation in isolated aortic rings and inhibited the inflammatory response (e.g., nitrite production) of RAW264.7 macrophages stimulated with endotoxin in a dose-dependent fashion. By analyzing the rate of CO release, we found that when the bromide at the 4-position of the 2-pyrone CORM-F3 is substituted with a chloride group [-4-(4-chloro-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F8)], the rate of CO release is significantly decreased (4.5-fold), and a further decrease is observed when the 4-and 6-positions are substituted with a methyl group [-4-(4-methyl-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F11)] or a hydrogen [-4-(4-chloro-2-pyrone)tricarbonyl iron (0) (CORM-F7)], respectively. Interestingly, the compounds containing halogens at the 4-position and the methyl at the 6-position of the 2-pyrone ring (CORM-F3 and CORM-F8) were found to be less cytotoxic compared with other CO-RMs when tested in RAW246.7 macrophages. Thus, iron-based carbonyls mediate pharmacological responses that are achieved through liberation of CO and the nature of the substituents in the organic ligand have a profound effect on both the rate of CO release and cytotoxicity.

Carbon Monoxide Releasing Molecule-2 Inhibits Pancreatic Stellate Cell Proliferation by Activating p38 Mitogen-Activated Protein Kinase/Heme Oxygenase-1 Signaling

“…In the present study, we investigated the effect of the HO-1 reaction product CO on PSC growth. Transition carbonyls acting as CO carriers could represent a way of supplying CO to tissues such as the pancreas in a more controllable fashion than achieved with CO gas, thereby reducing the risk of systemic toxicity (Motterlini et al, 2002;Sawle et al, 2006). We therefore used the carbon monoxide-releasing compound CORM-2 to assess the effects of CO on PSC proliferation.…”

“…CO-releasing molecules (CORMs) are metal carbonyl compounds capable of delivering defined amounts of CO into cellular systems, thereby reproducing the biological effects of CO derived from HO activity (Motterlini et al, 2002;Sawle et al, 2006). CORMs have shown antiproliferative effects in airway smooth muscle cells (Taille et al, 2005).…”

Differential Antibacterial Activity Against Pseudomonas aeruginosa by Carbon Monoxide-Releasing Molecules

“…These molecules provide a useful pharmacological tool to exploit the bioactive properties of CO and at the same time minimize the inherent toxicity of this gas (17,26,24,23). Numerous CORMs have been recently developed possessing different chemical structure and properties as well as different rates of CO release in cells and tissues (36,15,3,19,21). Essentially, two major groups of CO-RMs have been extensively studied so far: (i) metal carbonyls containing different types of transition metals (26,24); (ii) boranocarbonates that spontaneously release CO under physiological conditions (27,1,32).…”

Acyloxybutadiene Iron Tricarbonyl Complexes as Enzyme‐Triggered CO‐Releasing Molecules (ET‐CORMs)

“…The best of the compounds prepared to date (rac-13) exhibited a stronger activity, as for example cyclopentadienyl-based iron carbonyls ([(g-C 5 H 4 CO 2 Me)Fe(CO) 2 Br]) [28] or pyrone-based iron tricarbonyl complexes. [29] Although this compound displays a certain cytotoxicity, it is to the best of our knowledge the most potent CORM ever studied in this type of assay (30 % NO inhibition at 5 mm). [30] The concept introduced herein offers promising new options for the development of a new generation of CORMs, thus allowing a controlled and possibly even tissue-selective CO delivery.…”