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Redox-mediated carbon monoxide release from a manganese carbonyl-implications for physiological CO delivery by CO releasing moieties.

ABSTRACT: The dynamics of hydrogen peroxide reactions with metal carbonyls have received little attention. Given reports that therapeutic levels of carbon monoxide are released in hypoxic tumour cells upon manganese carbonyls reactions with endogenous H₂O₂, it is critical to assess the underlying CO release mechanism(s). In this context, a quantitative mechanistic investigation of the H₂O₂ oxidation of the water-soluble model complex fac-[Mn(CO)₃(Br)(bpCO₂)]^2-, (A, bpCO₂ ^2- = 2,2'-bipyridine-4,4'-dicarboxylate dianion) was undertaken under physiologically relevant conditions. Characterizing such pathways is essential to evaluating the viability of redox-mediated CO release as an anti-cancer strategy. The present experimental studies demonstrate that approximately 2.5 equivalents of CO are released upon H₂O₂ oxidation of A via pH-dependent kinetics that are first-order both in [A] and in [H₂O₂]. Density functional calculations were used to evaluate the key intermediates in the proposed reaction mechanisms. These pathways are discussed in terms of their relevance to physiological CO delivery by carbon monoxide releasing moieties.

SUBMITTER: Barrett JA

PROVIDER: S-EPMC8580448 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Redox and catalase-like activities of four widely used carbon monoxide releasing molecules (CO-RMs).

Project description:The pathophysiological roles of the endogenous signaling molecule, carbon monoxide (CO), have been extensively studied and validated in cell culture and animal models. Further, evidence supporting the therapeutic effects of CO in various human diseases has been mounting over the last two decades. Along this line, there has been intensive interest in developing various delivery forms including CO gas, CO in solution, metal-carbonyl complexes widely known as CO-releasing molecules (CO-RMs), and organic CO prodrugs. Among them, two ruthenium-based carbonyl complexes, CORM-2 and -3, occupy a very special place because they have been used in over 500 published studies. One of the mechanisms for CO's actions is known to be through attenuation of oxidative stress and regulation of production of reactive oxygen species (ROS). For this reason, it is important that CO delivery forms do not have intrinsic chemical redox properties. Herein, we describe our findings of catalase-like activities of CORM-2 and -3 in a CO-independent fashion, leading to the rapid degradation of hydrogen peroxide (H2O2) in PBS buffer (pH = 7.4) and in cell culture media. Further, we have found that CORM-2 and CORM-3 possess potent radical scavenging abilities. We have also studied two other widely used CO donors: CORM-401 and CORM-A1. Both showed chemical reactivity with ROS, but to a lesser degree than CORM-2 and -3. Because of the central role of ROS in some of the proposed mechanisms of actions for CO biology, the discovery of intrinsic chemical redox properties for these CO-RMs means that additional attention in designing proper controls is needed in future biological experiments using these CO-RMs for their CO-donating functions. Further, much more work is needed to understand the true implications of the chemical reactivity of these CO-RMs in cell-culture and animal-model studies of CO biology.

| S-EPMC8513939 | biostudies-literature

Designed iron carbonyls as carbon monoxide (CO) releasing molecules: rapid CO release and delivery to myoglobin in aqueous buffer, and vasorelaxation of mouse aorta.

Project description:The physiological roles of CO in neurotransmission, vasorelaxation, and cytoprotective activities have raised interest in the design and syntheses of CO-releasing materials (CORMs) that could be employed to modulate such biological pathways. Three iron-based CORMs, namely, [(PaPy(3))Fe(CO)](ClO(4)) (1), [(SBPy(3))Fe(CO)](BF(4))(2) (2), and [(Tpmen)Fe(CO)](ClO(4))(2) (3), derived from designed polypyridyl ligands have been synthesized and characterized by spectroscopy and X-ray crystallography. In these three Fe(II) carbonyls, the CO is trans to a carboxamido-N (in 1), an imine-N (in 2), and a tertiary amine-N (in 3), respectively. This structural feature has been correlated to the strength of the Fe-CO bond. The CO-releasing properties of all three carbonyls have been studied in various solvents under different experimental conditions. Rapid release of CO is observed with 2 and 3 upon dissolution in both aqueous and nonaqueous media in the presence and absence of dioxygen. With 1, CO release is observed only under aerobic conditions, and the final product is an oxo-bridged diiron species while with 2 and 3, the solvent bound [(L)Fe(CO)](2+) (where L = SBPy(3) or Tpmen) results upon loss of CO under both aerobic and anaerobic conditions. The apparent rates of CO loss by these CORMs are comparable to other CORMs such as [Ru(glycine)(CO)(3)Cl] reported recently. Facile delivery of CO to reduced myoglobin has been observed with both 2 and 3. In tissue bath experiments, 2 and 3 exhibit rapid vasorelaxation of mouse aorta muscle rings. Although the relaxation effect is not inhibited by the soluble guanylate cyclase inhibitor ODQ, significant inhibition is observed with the BK(Ca) channel blocker iberiotoxin.

| S-EPMC3073858 | biostudies-literature

Antimicrobial Activity of the Manganese Photoactivated Carbon Monoxide-Releasing Molecule [Mn(CO)3(tpa-?(3)N)](+) Against a Pathogenic Escherichia coli that Causes Urinary Infections.

Project description:AimsWe set out to investigate the antibacterial activity of a new Mn-based photoactivated carbon monoxide-releasing molecule (PhotoCORM, [Mn(CO)3(tpa-?(3)N)](+)) against an antibiotic-resistant uropathogenic strain (EC958) of Escherichia coli.ResultsActivated PhotoCORM inhibits growth and decreases viability of E. coli EC958, but non-illuminated carbon monoxide-releasing molecule (CORM) is without effect. NADH-supported respiration rates are significantly decreased by activated PhotoCORM, mimicking the effect of dissolved CO gas. CO from the PhotoCORM binds to intracellular targets, namely respiratory oxidases in strain EC958 and a bacterial globin heterologously expressed in strain K-12. However, unlike previously characterized CORMs, the PhotoCORM is not significantly accumulated in cells, as deduced from the cellular manganese content. Activated PhotoCORM reacts avidly with hydrogen peroxide producing hydroxyl radicals; the observed peroxide-enhanced toxicity of the PhotoCORM is ameliorated by thiourea. The PhotoCORM also potentiates the effect of the antibiotic, doxycycline.InnovationThe present work investigates for the first time the antimicrobial activity of a light-activated PhotoCORM against an antibiotic-resistant pathogen. A comprehensive study of the effects of the PhotoCORM and its derivative molecules upon illumination is performed and mechanisms of toxicity of the activated PhotoCORM are investigated.ConclusionThe PhotoCORM allows a site-specific and time-controlled release of CO in bacterial cultures and has the potential to provide much needed information on the generality of CORM activities in biology. Understanding the mechanism(s) of activated PhotoCORM toxicity will be key in exploring the potential of this and similar compounds as antimicrobial agents, perhaps in combinatorial therapies with other agents. Antioxid. Redox Signal. 24, 765-780.

| S-EPMC4876522 | biostudies-literature

Carbon monoxide--physiology, detection and controlled release.

Project description:Carbon monoxide (CO) is increasingly recognized as a cell-signalling molecule akin to nitric oxide (NO). CO has attracted particular attention as a potential therapeutic agent because of its reported anti-hypertensive, anti-inflammatory and cell-protective effects. We discuss recent progress in identifying new effector systems and elucidating the mechanisms of action of CO on, e.g., ion channels, as well as the design of novel methods to monitor CO in cellular environments. We also report on recent developments in the area of CO-releasing molecules (CORMs) and materials for controlled CO application. Novel triggers for CO release, metal carbonyls and degradation mechanisms of CORMs are highlighted. In addition, potential formulations of CORMs for targeted CO release are discussed.

| S-EPMC4072318 | biostudies-literature

Positive inotropic effects of carbon monoxide-releasing molecules (CO-RMs) in the isolated perfused rat heart.

Project description:Carbon monoxide (CO) generated by the enzyme haeme oxygenase-1 (HO-1) during the breakdown of haeme is known to mediate a number of biological effects. Here, we investigated whether CO liberated from two water soluble carbon monoxide-releasing molecules (CO-RMs) exerts inotropic effects on the myocardium.Rat isolated hearts perfused either at constant flow or constant pressure were used to test the effect of CO-RMs.CORM-3, a fast CO releaser, produced a direct positive inotropic effect when cumulative doses (3, 10 and 30 microg min(-1)) or a single dose (5 microM) were infused at either constant coronary pressure (CCP) or constant coronary flow (CCF). The inotropic effect mediated by CORM-3 was abolished by blockade of soluble guanylate cyclase or Na(+)/H(+) exchanger, but not by inhibitors of L-type Ca(2+) channels and protein kinase C. CORM-3 also caused a slight reduction in heart rate but did not alter coronary flow. In contrast, the slow CO releaser CORM-A1 produced significant coronary vasodilatation when given at the highest concentration (30 mug min(-1)) but exerted no effect on myocardial contractility or heart rate.A rapid CO release from CORM-3 exerts a direct positive inotropic effect on rat isolated perfused hearts, whereas CO slowly released by CORM-A1 had no effect on myocardial contractility but caused significant coronary vasodilatation. Both cGMP and Na(+)/H(+) exchange appear to be involved in this effect but further work is needed to determine the relative contribution of each pathway in CO-mediated inotropic effect.

| S-EPMC2014642 | biostudies-other

Manganese-catalyzed hydroboration of carbon dioxide and other challenging carbonyl groups.

Project description:Reductive functionalization of the C=O unit in carboxylic acids, carbonic acid derivatives, and ultimately in carbon dioxide itself is a challenging task of key importance for the synthesis of value-added chemicals. In particular, it can open novel pathways for the valorization of non-fossil feedstocks. Catalysts based on earth-abundant, cheap, and benign metals would greatly contribute to the development of sustainable synthetic processes derived from this concept. Herein, a manganese pincer complex [Mn(Ph2PCH2SiMe2)2NH(CO)2Br] (1) is reported to enable the reduction of a broad range of carboxylic acids, carbonates, and even CO2 using pinacolborane as reducing agent. The complex is shown to operate under mild reaction conditions (80-120?°C), low catalyst loadings (0.1-0.2?mol%) and runs under solvent-less conditions. Mechanistic studies including crystallographic characterisation of a borane adduct of the pincer complex (1) imply that metal-ligand cooperation facilitates substrate activation.

| S-EPMC6207666 | biostudies-literature

A novel carbon monoxide-releasing molecule fully protects mice from severe malaria.

Project description:Severe forms of malaria infection, such as cerebral malaria (CM) and acute lung injury (ALI), are mainly caused by the apicomplexan parasite Plasmodium falciparum. Primary therapy with quinine or artemisinin derivatives is generally effective in controlling P. falciparum parasitemia, but mortality from CM and other forms of severe malaria remains unacceptably high. Herein, we report the design and synthesis of a novel carbon monoxide-releasing molecule (CO-RM; ALF492) that fully protects mice against experimental CM (ECM) and ALI. ALF492 enables controlled CO delivery in vivo without affecting oxygen transport by hemoglobin, the major limitation in CO inhalation therapy. The protective effect is CO dependent and induces the expression of heme oxygenase-1, which contributes to the observed protection. Importantly, when used in combination with the antimalarial drug artesunate, ALF492 is an effective adjunctive and adjuvant treatment for ECM, conferring protection after the onset of severe disease. This study paves the way for the potential use of CO-RMs, such as ALF492, as adjunctive/adjuvant treatment in severe forms of malaria infection.

| S-EPMC3294911 | biostudies-literature

The carbon monoxide releasing molecule CORM-2 attenuates Pseudomonas aeruginosa biofilm formation.

Project description:Chronic infections resulting from biofilm formation are difficult to eradicate with current antimicrobial agents and consequently new therapies are needed. This work demonstrates that the carbon monoxide-releasing molecule CORM-2, previously shown to kill planktonic bacteria, also attenuates surface-associated growth of the gram-negative pathogen Pseudomonas aeruginosa by both preventing biofilm maturation and killing bacteria within the established biofilm. CORM-2 treatment has an additive effect when combined with tobramycin, a drug commonly used to treat P. aeruginosa lung infections. CORM-2 inhibited biofilm formation and planktonic growth of the majority of clinical P. aeruginosa isolates tested, for both mucoid and non-mucoid strains. While CORM-2 treatment increased the production of reactive oxygen species by P. aeruginosa biofilms, this increase did not correlate with bacterial death. These data demonstrate that CO-RMs possess potential novel therapeutic properties against a subset of P. aeruginosa biofilm related infections.

| S-EPMC3338523 | biostudies-literature

Norborn-2-en-7-ones as physiologically-triggered carbon monoxide-releasing prodrugs.

Project description:A prodrug strategy for the release of the gasotransmitter CO at physiological pH, based upon 3a-bromo-norborn-2-en-7-one Diels-Alder cycloadducts of 2-bromomaleimides and 2,5-dimethyl-3,4-diphenylcyclopentadienone has been developed. Examples possessing protonated amine and diamine groups showed good water solubility and thermal stability. Half-lives for CO-release in TRIS-sucrose buffer at pH 7.4 ranged from 19 to 75 min at 37 °C and 31 to 32 h at 4 °C. Bioavailability in rats was demonstrated by oral gavage and oCOm-21 showed a dose dependent vasorelaxant effect in pre-contracted rat aortic rings with an EC50 of 1.6 ± 0.9 ?M. Increased intracellular CO levels following oCOm-21 exposure were confirmed using a CO specific fluorescent probe.

| S-EPMC5609517 | biostudies-literature

Reactive oxygen species mediate bactericidal killing elicited by carbon monoxide-releasing molecules.

Project description:CO-releasing molecules (CO-RMs) were previously shown by us to be more potent bactericides than CO gas. This suggests a mechanism of action for CO-RM, which either potentiates the activity of CO or uses another CO-RM-specific effect. We have also reported that CORM-2 induces the expression of genes related to oxidative stress. In the present study we intend to establish whether the generation of reactive oxygen species by CO-RMs may indeed result in the inhibition of bacterial cellular function. We now report that two CO-RMs (CORM-2 and ALF062) stimulate the production of ROS in Escherichia coli, an effect that is abolished by addition of antioxidants. Furthermore, deletion of genes encoding E. coli systems involved in reactive oxygen species scavenging, namely catalases and superoxide dismutases, potentiates the lethality of CORM-2 due to an increase of intracellular ROS content. CORM-2 also induces the expression of the E. coli DNA repair/SOS system recA, and its inactivation enhances toxicity of CORM-2. Moreover, fluorescence microscopy images reveal that CORM-2 causes DNA lesions to bacterial cells. We also demonstrate that cells treated with CORM-2 contain higher levels of free iron arising from destruction of iron-sulfur proteins. Importantly, we show that CO-RMs generate hydroxyl radicals in a cell-free solution, a process that is abolished by scavenging CO. Altogether, we provide a novel insight into the molecular basis of CO-RMs action by showing that their bactericidal properties are linked to cell damage inflicted by the oxidative stress that they are able to generate.

| S-EPMC3143634 | biostudies-literature

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