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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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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

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

Hydrophilic CO-Releasing Material of PEGlyated Ruthenium Carbonyl Complex.

Project description:The poor water-solubility and instability of Ru(II) carbonyl complex hamper the therapeutic application as CO releasing materials (CO-RMs). To enhance the hydrophilicity and bio-utility of CO, a robust Ru(I) carbonyl sawhorse skeleton was grafted with water-soluble PEGylated sidearm. In this case, 12 PEGylated sawhorse Ru2(CO)4 complexes were prepared with satisfactory yields and characterized by IR and 1H- and 13C- NMR. X-ray diffraction analysis of CO-RM 8, 13 and 14 revealed the featured diruthenium sawhorse skeleton and PEGylated axial ligands. The flask-shaking method measures the water-solubility of CO-RMs, indicating that both bridging carboxylate ligands and PEGlyated axial ligands regulate the hydrophilicity of these CO-RMs. Under photolysis conditions, CO-RM 4-13 sustainable released therapeutic amounts of CO in the myoglobin assay. The correlation of the CO release kinetics and hydrophilicity of CO-RMs demonstrated that the more hydrophilic CO-RM released CO faster. The biological test found that the low cytotoxic CO-RM 4 showed a specific anticancer activity toward HT-29 tumour cells.

| S-EPMC9143562 | 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

CO-releasing Metal Carbonyl Compounds as Antimicrobial Agents in the Post-antibiotic Era.

Project description:The possibility of a "post-antibiotic era" in the 21st century, in which common infections may kill, has prompted research into radically new antimicrobials. CO-releasing molecules (CORMs), mostly metal carbonyl compounds, originally developed for therapeutic CO delivery in animals, are potent antimicrobial agents. Certain CORMs inhibit growth and respiration, reduce viability, and release CO to intracellular hemes, as predicted, but their actions are more complex, as revealed by transcriptomic datasets and modeling. Progress is hindered by difficulties in detecting CO release intracellularly, limited understanding of the biological chemistry of CO reactions with non-heme targets, and the cytotoxicity of some CORMs to mammalian cells.

| S-EPMC4521022 | biostudies-literature

Recent advances in carbon monoxide-releasing nanomaterials.

Project description:As an endogenous signaling molecule, carbon monoxide (CO) has emerged as an increasingly promising option regarding as gas therapy due to its positive pharmacological effects in various diseases. Owing to the gaseous nature and potential toxicity, it is particularly important to modulate the CO release dosages and targeted locations to elucidate the biological mechanisms of CO and facilitate its clinical applications. Based on these, diverse CO-releasing molecules (CORMs) have been developed for controlled release of CO in biological systems. However, practical applications of these CORMs are limited by several disadvantages including low stability, poor solubility, weak releasing controllability, random diffusion, and potential toxicity. In light of rapid developments and diverse advantages of nanomedicine, abundant nanomaterials releasing CO in controlled ways have been developed for therapeutic purposes across various diseases. Due to their nanoscale sizes, diversified compositions and modified surfaces, vast CO-releasing nanomaterials (CORNMs) have been constructed and exhibited controlled CO release in specific locations under various stimuli with better pharmacokinetics and pharmacodynamics. In this review, we present the recent progress in CORNMs according to their compositions. Following a concise introduction to CO therapy, CORMs and CORNMs, the representative research progress of CORNMs constructed from organic nanostructures, hybrid nanomaterials, inorganic nanomaterials, and nanocomposites is elaborated. The basic properties of these CORNMs, such as active components, CO releasing mechanisms, detection methods, and therapeutic applications, are discussed in detail and listed in a table. Finally, we explore and discuss the prospects and challenges associated with utilizing nanomaterials for biological CO release.

| S-EPMC10955104 | biostudies-literature

"CO in a pill": Towards oral delivery of carbon monoxide for therapeutic applications.

Project description:Along with the impressive achievements in understanding the endogenous signaling roles and mechanism(s) of action of carbon monoxide (CO), much research has demonstrated the potential of using CO as a therapeutic agent for treating various diseases. Because of CO's toxicity at high concentrations and the observed difference in toxicity profiles of CO depending on the route of administration, this review analyzes and presents the benefits of developing orally active CO donors. Such compounds have the potential for improved safety profiles, enhancing the chance for developing CO-based therapeutics. In this review, the difference between inhalation and oral administration in terms of toxicity, CO delivery efficiency, and the potential mechanism(s) of action is analyzed. The evolution from CO gas inhalation to oral administration is also extensively analyzed by summarizing published studies up to date. The concept of "CO in a pill" can be achieved by oral administration of novel formulations of CO gas or appropriate CO donors.

| S-EPMC8526413 | biostudies-literature

A series of Mn(i) photo-activated carbon monoxide-releasing molecules with benzimidazole coligands: synthesis, structural characterization, CO releasing properties and biological activity evaluation.

Project description:Five Mn(i) photo-activated carbon monoxide-releasing molecules (photo-CORMs) with benzimidazole coligands, namely [MnBr(CO)3L1] (1, L1 = 2-(2-pyridyl)benzimidazole), [Mn(CO)2L1(PPh3)2](ClO4) (2), [MnBr(CO)3L2] (3, L2 = 2,2'-bisbenzimidazole), [MnBr(CO)3L3]·CH3OH (4, L3 = 2,6-bis(benzimidazole-2'-yl)pyridine) and fac-[MnBr(CO)3L4] (5, L4 = 2,4-bis(benzimidazole-2'-yl) pyridine) were synthesized by reactions of MnBr(CO)5 with complexes L1-L4, respectively, and characterized via single crystal X-ray diffraction, elemental analysis, 1H-NMR, 13C-NMR, IR, UV-vis and fluorescence spectroscopy. The CO-release properties of 1-5 were investigated using the myoglobin assay and CO detection, and the results show that all of the complexes could release CO rapidly upon exposure to 365 nm UV light. Comparing their half-lives of CO release, we found that increasing the degree of unsaturation and conjugation of the ligand frame could be advantageous for prolonging the time of CO-release, and that the luminescence intensity of 1-5 could gradually be enhanced. The cellular fluorescence imaging tests demonstrate that these Mn(i) photo-CORMs can be taken up by human liver cells (HL-7702) and liver cancer cells (SK-Hep1), and exhibit good capabilities for bioimaging. A cell viability assay for SK-Hep1 shows that the anticancer activity of 3 is better than that of other complexes.

| S-EPMC9065806 | biostudies-literature

Photo-Responsive Micelles with Controllable and Co-Release of Carbon Monoxide, Formaldehyde and Doxorubicin.

Project description:Endogenous gases have attracted much attention due to their potent applications in disease therapies. The combined therapy, including gaseous molecules and other medicines that can create synergistic effects, is a new way for future treatment. However, due to the gaseous state, gas utilization in medical service is still limited. To pave the way for future usage, in this work, an amphiphilic block copolymer containing nitrobenzyl ether, 3-hydroxyflavone (3-HF) derivatives and ether linker was constructed. The nitrobenzyl ether group endows the polymer with a photo-responsive character. Upon light illumination, 3-HF derivatives can be triggered for carbon monoxide (CO) release. The ether linker can also be released emitting formaldehyde (FA). The self-assembly induced micelle can encompass medicine, e.g., doxorubicin (DOX), into it and a controlled release of DOX can be realized upon light illumination. As far as we know, there is no report on the combination donor of CO and DOX and this is the first attempt on the co-release of CO, FA and DOX.

| S-EPMC9230906 | biostudies-literature

Manganese dioxide nanosheets-based redox/pH-responsive drug delivery system for cancer theranostic application.

Project description:The aim of this study was to construct redox- and pH-responsive degradable manganese dioxide (MnO2) nanosheets for cancer theranostic application. The small MnO2 nanosheets were synthesized, and then functionalized by hyaluronic acid (HA), demonstrating excellent stability and tumor-targeting ability. Cisplatin (cis-diamminedichloroplatinum [CDDP]) was absorbed by the nanosheets through a physical action, which was designed as MnO2/HA/CDDP. The prepared MnO2/HA/CDDP formulation was able to efficiently deliver CDDP to tumor cells in vitro and in vivo, resulting in improved therapeutic efficiency. Subsequently, they were triggered by lower pH and higher level of reduced glutathione to generate Mn(2+), enabling magnetic resonance imaging. The smart multifunctional system combining efficient magnetic resonance imaging and chemotherapy has the potential to be used as a tumor-targeting theranostic nanomedicine.

| S-EPMC4857809 | biostudies-literature

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