CO-releasing Properties Research Articles

Nanodiamond mediated co-delivery of doxorubicin and malaridine to maximize synergistic anti-tumor effects on multi-drug resistant MCF-7/ADR cells.

Co-delivery of two or more chemotherapeutic agents via nanocarriers can provide an effective approach to maximize synergistic or additive effects. In this work, we developed novel nanodiamond (ND) based nanoparticle co-loading of doxorubicin (DOX) and malaridine (MAL) for treatment of MCF-7/ADR cells by virtue of the good biocompatibility, high drug loading capacity and pH-responsive drug release properties of NDs. The combination index (CI) was the smallest, 0.17, for DOX and MAL against MCF-7/ADR cells, when their ratio was 5 : 1, showing the greatest synergistic effects. (DOX + MAL)@NDs or FA-PEG-DOX/(DOX + MAL)@NDs with different ratios of DOX to MAL (4 : 1, 5 : 1 and 6 : 1) were prepared by simple physical adsorption of DOX, MAL and FA-PEG-DOX. Among them, (DOX + MAL)@NDs with the mass ratio of 5 : 1 had the smallest CI of 0.08. The concentrations of DOX and MAL for (DOX + MAL)@NDs producing 50% growth inhibition were 1.90 and 0.35 μg mL-1, respectively, smaller than the 50% inhibitory concentrations for DOX@NDs and MAL@NDs (10.75 and 4.38 μg mL-1) and for free DOX and free MAL (49.65 and 9.03 μg mL-1). (DOX + MAL)@NDs were not stable in water, FA-PEG-DOX/(DOX + MAL)@NDs could stay stable in water for 24 h due to steric repulsion effects offered by PEG, which also compromised their cytotoxicities to some extent. (DOX + MAL)@NDs or FA-PEG-DOX/(DOX + MAL)@NDs presented faster DOX and MAL co-release at pH 5.5 than 7.4. The high anti-tumor efficacy suggested that the ND mediated DOX and MAL co-delivery system could be promising for the treatment of multi-drug resistant cancer.

Visible light photoactivatable CO releasing manganese (I) tricarbonyl complexes: Experimental and DFT studies

The reaction between [Mn(CO)5Br] and antibacterial drugs (Nifuroxazide (NIF) and Nitazoxanide (NTZ)) afforded fac-[MnBr(CO)3(NIF)] (1) and fac-[MnBr(CO)3(NTZ)2] (2) complexes, which were characterized by different analytical and spectral tools. The photo-induced CO releasing properties and the ability of the metal carbonyls to drive CO to the myoglobin solution were investigated. The green-light (525 nm) illumination of the DMSO solution of 1 for 20 min gave rise to the maximum amount of CO. Compared with the DMSO solution of 1, the rate of CO release from the 80% aqueous-DMSO mixed media is slower, and the plateau is reached upon the illumination for 140 min. On the contrast, a clear isosbestic point is developed during the storing of the DMSO solution of 2 for 6 h, which reflects its instability. To drive CO from 2 to myoglobin solution, the energy of the green light was not sufficient. However, the grown of the bands corresponding to the formation of carboxy-myoglobin species is stopped after 50 min of the irradiation at 468 nm and 36 min at 410 nm. The electronic structures and the related electronic transitions have been calculated by TD-DFT/B3LYP (or CAM-B3LYP)/LANL2DZ methods. The spectra calculated by the hybrid exchange-correlation functional CAM-B3LYP with a long range correction term are more closed to the experimental findings. The remarkable toxicity of 2 against the tested microbes, with respect to the free drug, may be attributed to the change of the lipophilicity of free NTZ upon the complex formation as well as the releasing of CO upon the incubation in dark.

CO-releasing properties and anticancer activities of manganese complexes with imidazole/benzimidazole ligands

Carbon monoxide (CO) is an important signaling molecule which plays significant roles in the pathogenesis of cancer. CO is produced by enzymatic degradation of heme in mammals. Heme oxygenase 1 (HO-1) catalyzes the breakdown of heme into CO, ferrous iron, and biliverdin. CO induces HO-1 and inhibits cell proliferation. Cancer cells exposed to several stress factors (hypoxia, reactive oxygen species, cis-platin, and oxidative stress), and HO-1 displays cytoprotective role against oxidative stress and inhibits apoptosis, metastases, angiogenesis, and cell proliferation processes. Therefore, metal containing CO-releasing molecules (CORMs) have been designed as an effective cancer treatment strategy. CORMs are responsible for releasing controlled amounts of CO to cells and tissues. Thus, we synthesized [Mn(CO)3(bpy)L]X manganese containing CORMs [bpy = 2,2′-bipyridine, X = hexafluorophosphate (PF6), trifluoromethanesulfonate (OTf), L = imidazole, methylimidazole, benzimidazole, N-benzylbenzimidazole, N-(4-chlorobenzyl)benzimidazole] to release CO in human invasive ductal breast (MCF-7) cell line. In vitro experiments indicated that the compounds inhibited cell proliferation and exhibited cytotoxic effect on breast cancer cells. Moreover, side groups of the compounds enhanced the anticancer effects in MCF-7 cell line. These manganese containing CORMs gave promising results and may be used as a drug template for effective treatment of invasive ductal breast carcinoma.

Structure, CO-releasing property, electrochemistry, DFT calculation, and antioxidant activity of benzimidazole derivative substituted [Mn(CO)3(bpy)L]PF6 type novel manganese complexes

Metal carbonyl complexes are prominent group organometallic compounds because of their applications in industrial and pharmaceutical chemistry. In recent years, metal carbonyl complexes have been accepted major for storage and transportation of carbon monoxide which is an important signaling molecule significantly in pathogenesis of some diseases. Thus, we designed and synthesized novel manganese(I)carbonyl complexes with general formula [Mn(CO)3(bpy)L]PF6 (bpy=2,2-bipyridyl, L=N-(2-chlorobenzyl)benzimidazole, N-(2-methoxybenzyl)benzimidazole, N-(2-methylbenzyl)benzimidazole). The complex molecules were characterized by LC-MS, 1H-NMR, 13C-NMR, IR spectroscopy methods and elemental analysis. The CO-releasing properties, antioxidant activities and redox properties of these complexes were investigated. The DFT/TDDFT analyses were made by ORCA package program.

Carbon monoxide-releasing properties and DFT/TDDFT analysis of [Mn(CO)3(bpy)L]PF6 type novel manganese complexes

Novel manganese(I)carbonyl complexes of the general formula [Mn(CO)3(bpy)L]PF6 (bpy = 2,2-bipyridyl, L = N-(2-methylbenzyl)imidazoline, N-(3-methylbenzyl)imidazoline, N-(4-methylbenzyl)imidazoline, N-(2,4,6-trimethylbenzyl)imidazoline) were synthesized and characterized by analytical (LC-MS spectrometry and elemental analysis) and spectroscopic (1H NMR, 13C NMR, cosy2D-NMR, infrared) methods. The CO-releasing properties of these complexes were investigated with myoglobin assay. The DFT/TDDFT calculations were made by ORCA package program with both BP86 and B3LYP functionals.

A combined experimental and DFT investigation on the structure and CO-releasing properties of mono and binuclear fac-ReI(CO)3 complexes with 5-pyridin-2-ylmethylene-amino uracils.

The synthesis, structure and CO-releasing properties of a number of new tricarbonyl rhenium(i) complexes with 5-substituted-6-amino-1,3-dimethyluracils are reported and their structural features discussed on the basis of both spectral and X-ray crystallographic analyses. The 5-substituent library includes -N[double bond, length as m-dash]CH-2py (DAAUPic) and -CH[double bond, length as m-dash]N-N[double bond, length as m-dash]CH-2py (FDUHzPic) as additional metal binding components and chloride, acetonitrile or pyridine acting as ancillary ligands. The compounds have been identified by elemental analysis, NMR, MS and IR spectroscopy. In addition, [ReCl(CO)3(DAAUPic)], [Re(CO)3(FDUHzPic)py]ClO4, [Re(CO)3(FDUHzPic)py]PF6, [Re2Cl2(CO)6(FDUHzPic)] and [Re2Cl(CO)6(FDUHzPicH-1)(H2O)] structures have been solved by X-ray diffraction methods. These studies have clearly shown that the preferred coordination mode to rhenium takes place through the (N1F,N52)-pyridin-2-yl-methyleneamine moiety, the uracil coordinative availability (O4-N51 or N6-N51) being used only to bind the second metal center. The CO-releasing ability of these rhenium compounds has been investigated by the reaction with myoglobin; the corresponding studies have revealed that two of the mononuclear complexes and their related binuclear analogues are able to release CO to a moderate extent. This ability has also been theoretically assessed through a QTAIM analysis. The results, although non-conclusive, may explain somehow possible different preferences in CO releasing power after a comparison between the nature of Re-CO links in mononuclear and binuclear compounds.

Visible-light-induced release of CO by thiolate iron(iii) carbonyl complexes bearing N,C,S-pincer ligands.

Iron(iii) carbonyl complexes are stabilized by a pincer ligand containing pyridine-N, phenyl-C and thiolate-S donors and two axial phosphine ligands. The N,C,S-pincer iron(iii) carbonyl complexes show CO-releasing properties induced by visible light.

CORM-EDE1: A Highly Water-Soluble and Nontoxic Manganese-Based photoCORM with a Biogenic Ligand Sphere.

[Mn(CO)5Br] reacts with cysteamine and 4-amino-thiophenyl with a ratio of 2:3 in refluxing tetrahydrofuran to the complexes of the type [{(OC)3Mn}2(μ-SCH2CH2NH3)3]Br2 (1, CORM-EDE1) and [{(OC)3Mn}2(μ-SC6H4-4-NH3)3]Br2 (2, CORM-EDE2). Compound 2 precipitates during refluxing of the tetrahydrofuran solution as a yellow solid whereas 1 forms a red oil that slowly solidifies. Recrystallization of 2 from water yields the HBr-free complex [{(OC)3Mn}2(μ-S-C6H4-4-NH2)2(μ-SC6H4-4-NH3)] (3). The n-propylthiolate ligand (which is isoelectronic to the bridging thiolate of 1) leads to the formation of the di- and tetranuclear complexes [(OC)4Mn(μ-S-nPr)2]2 and [(OC)3Mn(μ-S-nPr)]4. CORM-EDE1 possesses ideal properties to administer carbon monoxide to biological and medicinal tissues upon irradiation (photoCORM). Isolated crystalline CORM-EDE1 can be handled at ambient and aerobic conditions. This complex is nontoxic, highly soluble in water, and indefinitely stable therein in the absence of air and phosphate buffer. CORM-EDE1 is stable as frozen stock in aqueous solution without any limitations, and these stock solutions maintain their CO release properties. The reducing dithionite does not interact with CORM-EDE1, and therefore, the myoglobin assay represents a valuable tool to study the release kinetics of this photoCORM. After CO liberation, the formation of MnHPO4 in aqueous buffer solution can be verified.

Synthesis and characterization of heteroscorpionate-based manganese carbonyl complexes as CO-releasing molecules

Tricarbonylmanganese(I) complexes of the heteroscorpionate ligand 3,3-bis(3,5-dimethylpyrazol-1-yl)propionate (bpzp) and the tris-imidazole complex fac-[Mn(CO)3(HIm)3]Br were prepared. These and the literature-know tricarbonyl complexes based on bis(3,5-dimethylpyrazol-1-yl)acetate (bdmpza), bis(pyrazol-1-yl)acetate (bpza), 3,3-bis(3,5-dimethylpyrazol-1-yl)propionate (bdmpzp) and fac-[MnBr(CO)3(Hpz)2] were tested for their potential to act as photoactivable CO-releasing molecules (PhotoCORMs) by the UV/Vis spectroscopy based myoglobin assay. The manganese(I) complexes of the monodentate imidazole and pyrazole ligands lack stability in solution and show fast CO release already in the dark. In the four heteroscorpionate complexes, the substitution pattern and the chain length of the carboxylate moiety have a pronounced influence on the stability in solution and the CO release properties.

Synthesis, Spectroscopic Properties, and Photoinduced CO-Release Studies of Functionalized Ruthenium(II) Polypyridyl Complexes: Versatile Building Blocks for Development of CORM–Peptide Nucleic Acid Bioconjugates

A series of ruthenium(II) dicarbonyl complexes of formula [RuCl2(L)(CO)2] (L = bpy(CH3,CH3) = 4,4'-dimethyl-2,2'-bipyridine, bpy(CH3,CHO) = 4'-methyl-2,2'-bipyridine-4-carboxyaldehyde, bpy(CH3,COOH) = 4'-methyl-2,2'-bipyridine-4-carboxylic acid, CppH = 2-(pyridin-2-yl)pyrimidine-4-carboxylic acid, dppzcH = dipyrido[3,2-a:2',3'-c]phenazine-11-carboxylic acid), and [RuCl(L)(CO)2](+) (L = tpy(COOH) = 6-(2,2':6',2″-terpyridine-4'-yloxy)hexanoic acid) has been synthesized. In addition, a high-yield synthesis of a peptide nucleic acid (PNA) monomer containing the 2-(pyridin-2-yl)pyrimidine ligand was also developed, and this compound was used to prepare the first Ru(II) dicarbonyl complex, [RuCl2(Cpp-L-PNA)(CO)2],(Cpp-L-PNA = tert-butyl-N-[2-(N-9-fluorenylmethoxycarbonyl)aminoethyl]-N-[6-(2-(pyridin-2-yl)pyrimidine-4-carboxamido)hexanoyl]glycinate) attached to a PNA monomer backbone. Such metal-complex PNA-bioconjugates are attracting profound interest for biosensing and biomedical applications. Characterization of all complexes has been undertaken by IR and NMR spectroscopy, mass spectrometry, elemental analysis, and UV-vis spectroscopy. Investigation of the CO-release properties of the Ru(II) complexes in water/dimethyl sulfoxide (49:1) using the myoglobin assay showed that they are stable under physiological conditions in the dark for at least 60 min and most of them even for up to 15 h. In contrast, photoinduced CO release was observed upon illumination at 365 nm, the low-energy shoulder of the main absorption maximum centered around 300 nm, establishing these compounds as a new class of PhotoCORMs. While the two 2,2'-bipyridine complexes release 1 equiv of CO per mole of complex, the terpyridine, 2-(2'-pyridyl)pyrimidine, and dipyrido[3,2-a:2',3'-c]phenazine complexes are less effective CO releasers. Attachment of the 2-(2'-pyridyl)pyrimidine complex to a PNA backbone as in [RuCl2(Cpp-L-PNA)CO2] did not significantly change the spectroscopic or CO-release properties compared to the parent complex. Thus, a novel class of Ru(II)-based PhotoCORMs has been established which can be coupled to carrier delivery vectors such as PNA to facilitate cellular uptake without loss of the inherent CORM properties of the parent compound.

Next Generation PhotoCORMs: Polynuclear Tricarbonylmanganese(I)-Functionalized Polypyridyl Metallodendrimers

The first CO-releasing metallodendrimers, based on polypyridyl dendritic scaffolds functionalized with Mn(CO)3 moieties, of the general formula [DAB-PPI-{MnBr(bpy(CH3,CH═N))(CO)3}n], where DAB = 1,4-diaminobutane, PPI = poly(propyleneimine), bpy = bipyridyl, and n = 4 for first- or n = 8 for second-generation dendrimers, were synthesized and comprehensively characterized by analytical (HR-ESI mass spectrometry and elemental analysis) and spectroscopic ((1)H, (13)C{(1)H}-NMR, infrared, and UV/vis spectroscopy) methods. The CO-release properties of these compounds were investigated in pure buffer and using the myoglobin assay. Both metallodendrimer generations are stable in the dark in aqueous buffer for up to 16 h but show photoactivated CO release upon excitation at 410 nm, representing a novel class of macromolecular photoactivatable CO-releasing molecules (PhotoCORMs). No scaling effects were observed since both metallodendrimers release ∼65% of the total number of CO ligands per molecule, regardless of the generation number. In addition, the mononuclear model complex [MnBr(bpy(CH3,CH═NCH2CH2CH3))(CO)3] was prepared and comprehensively studied, including DFT/TDDFT calculations. These metallodendrimer-based PhotoCORMs afford new methods of targeted delivery of large amounts of carbon monoxide to cellular systems.

Vasorelaxing effects and inhibition of nitric oxide in macrophages by new iron-containing carbon monoxide-releasing molecules (CO-RMs)

Carbon monoxide-releasing molecules (CO-RMs) are a class of organometallo carbonyl complexes capable of delivering controlled quantities of CO gas to cells and tissues thus exerting a broad spectrum of pharmacological effects. Here we report on the chemical synthesis, CO releasing properties, cytotoxicity profile and pharmacological activities of four novel structurally related iron-allyl carbonyls. The major difference among the new CO-RMs tested was that three compounds (CORM-307, CORM-308 and CORM-314) were soluble in dimethylsulfoxide (DMSO), whereas a fourth one (CORM-319) was rendered water-soluble by reacting the iron-carbonyl with hydrogen tetrafluoroborate. We found that despite the fact all compounds liberated CO, CO-RMs soluble in DMSO caused a more pronounced toxic effect both in vascular and inflammatory cells as well as in isolated vessels. More specifically, iron carbonyls soluble in DMSO released CO with a fast kinetic and displayed a marked cytotoxic effect in smooth muscle cells and RAW 247.6 macrophages despite exerting a rapid and pronounced vasorelaxation ex vivo. In contrast, CORM-319 that is soluble in water and liberated CO with a slower rate, preserved smooth muscle cell viability, relaxed aortic tissue and exerted a significant anti-inflammatory effect in macrophages challenged with endotoxin. These data suggest that iron carbonyls can be used as scaffolds for the design and synthesis of pharmacologically active CO-RMs and indicate that increasing water solubility and controlling the rate of CO release are important parameters for limiting their potential toxic effects.

CO Release from Norbornadiene Iron(0) Tricarbonyl Complexes: Importance of Ligand Dissociation

An investigation into the CO-releasing properties of a range of iron tricarbonyl and chromium and molybdenum tetracarbonyl complexes is presented. Iron tricarbonyl complexes containing the 2,5-bicyclo[2.2.1]heptene (norbornadiene) ligand are shown to be effective CO-releasing molecules, in which the rate and extent of CO release may be modulated by modification of the norbornadiene framework. Species containing the parent norbornadiene and those with a substituent at the 7-position of the organic ligand exhibit CO release; those containing ester substituents at the 2- and/or 3-positions do not. A mechanism for CO release in this species is proposed which involves initial norbornadiene dissociation, a suggestion which is supported by the spectroscopic data and the observation that the addition of excess substituted norbornadiene retards the rate of CO release. CO release from the diester-containing norbornadiene complex may be promoted photochemically, and cell viability studies indicate that in the absenc...

Synthesis, Structures, and CO Releasing Properties of two Tricarbonyl Manganese(I) Complexes

Abstract[MnBr(CO)5] reacts with one equivalent each of 1, 3, 5‐triaza‐7‐phosphaadamantane (PTA) and sodium diethyldithiocarbamate to afford the yellow MnI complex fac‐[Mn(S2CNEt2)(PTA)(CO)3]. Similarly, the same MnI precursor reacts with the sodium salt ofL‐histidine to give the tricarbonyl manganese(I) complex fac‐[Mn(his)(CO)3] in good yield as a yellow solid. Both compounds were spectroscopically and structurally characterised. The histidinato complex is soluble in water and its aqueous solutions are stable for more than 24 h. The CO releasing properties of the histidinato complex were studied with the myoglobin assay and establish this compound as a novel PhotoCORM, which liberates one of the three carbonyl ligands upon irradiation.

Silicium Dioxide Nanoparticles As Carriers for Photoactivatable CO-Releasing Molecules (PhotoCORMs)

Silicium dioxide nanoparticles of about 20 nm diameter containing azido groups at the surface were prepared by emulsion copolymerization of trimethoxymethylsilane and (3-azidopropyl)triethoxysilane and studied by transmission electron microscopy (TEM). A photoactivatable CO-releasing molecule (PhotoCORM) based on [Mn(CO)(3)(tpm)](+) (tpm = tris(pyrazolyl)methane) containing an alkyne-functionalized tpm ligand was covalently linked to the silicium dioxide nanoparticles via the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC "click" reaction). The surface functionalization of the particles with azido groups and manganese CORMs was analyzed by UV-vis, IR, (1)H and (13)C CP-MAS NMR spectroscopies as well as energy-dispersive X-ray spectroscopy (EDX). The myoglobin assay was used to demonstrate that the CORM-functionalized nanoparticles have photoinducible CO-release properties very similar to the free complex. In the future, such functionalized silicium dioxide nanoparticles might be utilized as delivery agents for CORMs in solid tumors.

Designed Iron Carbonyls as Carbon Monoxide (CO) Releasing Molecules: Rapid CO Release and Delivery to Myoglobin in Aqueous Buffer, and Vasorelaxation of Mouse Aorta

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.

Reactivity of 17 e− Complex [ReIIBr4(CO)2]2− with Bridging Aromatic Ligands. Characterization and CO-Releasing Properties

Carbon monoxide releasing molecules (CO-RMs) are a newly emerging class of compounds of pharmacological interest. Among the transition metal-based CO-RMs, 17-electron complexes of general formula cis-trans-[Re(II)(CO)(2)Br(2)L(2)] are promising candidates but their poor hydrophilicity hampers future applications. In an effort to increase water solubility of d(5) dicarbonyl rhenium CO-RMs, the reaction of the cis-[Re(II)(CO)(2)Br(4)](2-) anion with bridging aromatic ligands of the pyridine and diazine type was investigated. Mononuclear and binuclear complexes are presented and it is shown that the nature of the bridging ligand critically dictates the formation of either species. Most complexes retained their fundamental CO-releasing properties. The synthesis of the molecules together with structural, spectroscopic and theoretical details are discussed.

CO-releasing properties of cis-trans-[ReII(CO)2Br2L2]n complexes

CO-releasing properties of cis-trans-[ReII(CO)2Br2L2]n complexes

Syntheses, structural characterization and CO releasing properties of boranocarbonate [H3BCO2H]− derivatives

CO plays an important role in biological processes and molecules which release CO in a controllable way could therefore be used for medicinal purposes. Beside organometallic carbonyl complexes, boranocarbonate [H(3)BCO(2)H](-) is one of the most promising candidates but releases CO too rapidly. In order to delay the CO release, we have prepared boranocarbamates [H(3)BCONH-R](-) from [H(3)BCO(2)H](-) which comprise histamine, morpholine, aniline and ethylene-diamine bound via amides to the {H(3)BCO} moiety. The syntheses of the new derivatives is described together with their structural characterization. These compounds release CO at a much slower rate than the parent compound and are therefore potential CO releasing molecules for biological and medicinal application.

Regulation of Drk1 Channels by Carbon Monoxide and Carbon Monoxide-Releasing Molecule-2

Carbon monoxide is a poisonous gas that is also syntethized in several tissues in the body, where it acts as a signaling molecule. CO has been shown to regulate ion channels such as voltage-dependent calcium channels (VDCC) and large-conductance calcium-activated potassium (BK) channels, a mechanism which is important for oxygen sensing in the carotid body. The Kv2.1 channel has been implicated with oxygen sensing in the pulmonary arteries and the ductus arteriosus, a process which may be regulated by carbon monoxide. We therefore investigated the effects of carbon monoxide and tricarbonyl dichloro-ruthenium dimmer (CORM-2), a widely used carbon monoxide releasing molecule, on the Kv2.1 channel. We found that, unlike with VDCC and BK channels, CORM-2 does not have the same effect as carbon monoxide: CO does not have an effect on the channel, while CORM-2 acts as an intracellular allosteric inhibitor of channel function. CORM-2 slows channel activation and deactivation kinetics by reducing the voltage-dependence of the rate constants. It also reduces overall open probability without affecting steady-state voltage-dependence. Manganese-decacarbonyl, another carbon-releasing molecule also does not have an effect on the Kv2.1, while ruthenium red seems to have biphasic effects, one mimicking the action of CORM-2 on the channel and the other representing voltage-dependent pore block, which suggests that CORM-2's actions on the Kv2.1 are independent from its CO-releasing properties.