BIOACTIVE PROPERTIES OF IRON-CONTAINING CARBON

Carbon monoxide-releasing molecules (CO-RMs) are compounds capable of delivering controlled amounts of CO within a cellular environment. Ruthenium-based carbonyls (CORM-2 and CORM-3) and boronacorbonates (CORM-A1) 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 CORM-F3, an irontricarbonyl complex which 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 (eg 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 in CORM-F3 is substituted with a chloride group (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 (CORM-F11) or a hydrogen (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 to 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 Nitride as a Ligand: Selective Hydrogenation of Terminal Alkenes using [(η5-C5Me5)IrCl(g-C3N4-κ2N, N')]Cl : Selective Hydrogenation of Terminal Alkenes using [(η5-C5Me5)IrCl(g-C3N4-κ2N, N')]Cl

Anchoring a homogeneous catalyst onto a heterogeneous support facilitates separation of the product from the catalyst, and catalyst-substrate interactions can also modify reactivity. Herein we describe the synthesis of composite materials comprising carbon nitride (g-C 3 N 4 ) as the heterogeneous support and the well established homogeneous catalyst moiety [Cp*IrCl] + (where Cp* = η 5 -C 5 Me 5 ), commonly used for catalytic hydrogenation. Coordination of [Cp*IrCl] + to g-C 3 N 4 occurs directly at exposed edge sites with a κ 2 N, N' binding motif, leading to a primary inner coordination sphere analogous to known homogeneous complexes of the general class [Cp*IrCl(NN-κ 2 N, N' )] + (where N, N' = a bidentate nitrogen ligand). Hydrogenation of unsaturated substrates using the composite catalyst is selective for terminal alkenes, which is attributed to the restricted steric environment of the outer coordination sphere at the edge-sites of g-C 3 N 4

Bioactive properties of iron-containing carbon monoxide-releasing molecules

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 η-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

Redox-switchable siderophore anchor enables reversible artificial metalloenzyme assembly

Artificial metalloenzymes that contain protein-anchored synthetic catalysts are attracting increasing interest. An exciting, but still unrealized advantage of non-covalent anchoring is its potential for reversibility and thus component recycling. Here we present a siderophore–protein combination that enables strong but redox-reversible catalyst anchoring, as exemplified by an artificial transfer hydrogenase (ATHase). By linking the iron(iii)-binding siderophore azotochelin to an iridium-containing imine-reduction catalyst that produces racemic product in the absence of the protein CeuE, but a reproducible enantiomeric excess if protein bound, the assembly and reductively triggered disassembly of the ATHase was achieved. The crystal structure of the ATHase identified the residues involved in high-affinity binding and enantioselectivity. While in the presence of iron(iii), the azotochelin-based anchor binds CeuE with high affinity, and the reduction of the coordinated iron(iii) to iron(ii) triggers its dissociation from the protein. Thus, the assembly of the artificial enzyme can be controlled via the iron oxidation state

Luminescent iridium complexes for detection of molybdate

Reactions of [Ir(CŸN)2Cl]2 [HCŸN = 2-(3-R-phenyl)pyridine, 2-(3-R-phenylpyrazole) R = H, Me] with Me2-phencat give luminescent complexes [Ir(CŸN)2(Me2-phencat)][PF6] (Me2-2a, b, c)[PF6]. Deprotection of the methoxy groups with BBr3 is problematic as simultaneous bromination of the cyclometallated phenyl groups occurs. However, deprotection of Me2-phencat with BBr3 followed by complexation with [Ir(CŸN)2Cl]2 gives luminescent complexes [Ir(CŸN)2(H2-phencat)][PF6] (H2-3a, c)[PF6], which are luminescent sensors for molybdate

The Pneumococcal Iron Uptake Protein a (PiuA) Specifically Recognizes Tetradentate FeIIIbis- and Mono-Catechol Complexes

Streptococcus pneumoniae (Spn) is an important Gram-positive human pathogen that causes millions of infections worldwide with an increasing occurrence of antibiotic resistance. Fe acquisition is a crucial virulence determinant in Spn; further, Spn relies on exogenous FeIII-siderophore scavenging to meet nutritional Fe needs. Recent studies suggest that the human catecholamine stress hormone, norepinephrine (NE), facilitates Fe acquisition in Spn under conditions of transferrin-mediated Fe starvation. Here we show that the solute binding lipoprotein PiuA from the piu Fe acquisition ABC transporter PiuBCDA, previously described as an Fe-hemin binding protein, binds tetradentate catechol FeIII complexes, including NE and the hydrolysis products of enterobactin. Two protein-derived ligands (H238, Y300) create a coordinately-saturated FeIII complex, which parallel recent studies in the Gram-negative intestinal pathogen Campylobacter jejuni. Our in vitro studies using NMR spectroscopy and 54Fe LC-ICP-MS confirm the FeIII can move from transferrin to apo-PiuA in a NE-dependent manner. Structural analysis of PiuA FeIII-bis-catechol and GaIII-bis-catechol and GaIII-(NE)2 complexes by NMR spectroscopy reveals only localized structural perturbations in PiuA upon ligand binding, largely consistent with recent descriptions of other solute binding proteins of type II ABC transporters. We speculate that tetradentate FeIII complexes formed by mono- and bis-catechol species are important Fe sources in Gram-positive human pathogens, since PiuA functions in the same way as SstD from Staphylococcus aureus

Bacteria in an intense competition for iron : Key component of the Campylobacter jejuni iron uptake system scavenges enterobactin hydrolysis product

To acquire essential Fe(III), bacteria produce and secrete siderophores with high affinity and selectivity for Fe(III) to mediate its uptake into the cell. Here, we show that the periplasmic binding protein CeuE of Campylobacter jejuni, which was previously thought to bind the Fe(III) complex of the hexadentate siderophore enterobactin (Kd ∼ 0.4 ± 0.1 µM), preferentially binds the Fe(III) complex of the tetradentate enterobactin hydrolysis product bis(2,3-dihydroxybenzoyl-l-Ser) (H5-bisDHBS) (Kd = 10.1 ± 3.8 nM). The protein selects Λ-configured [Fe(bisDHBS)](2-) from a pool of diastereomeric Fe(III)-bisDHBS species that includes complexes with metal-to-ligand ratios of 1:1 and 2:3. Cocrystal structures show that, in addition to electrostatic interactions and hydrogen bonding, [Fe(bisDHBS)](2-) binds through coordination of His227 and Tyr288 to the iron center. Similar binding is observed for the Fe(III) complex of the bidentate hydrolysis product 2,3-dihydroxybenzoyl-l-Ser, [Fe(monoDHBS)2](3-) The mutation of His227 and Tyr288 to noncoordinating residues (H227L/Y288F) resulted in a substantial loss of affinity for [Fe(bisDHBS)](2-) (Kd ∼ 0.5 ± 0.2 µM). These results suggest a previously unidentified role for CeuE within the Fe(III) uptake system of C. jejuni, provide a molecular-level understanding of the underlying binding pocket adaptations, and rationalize reports on the use of enterobactin hydrolysis products by C. jejuni, Vibrio cholerae, and other bacteria with homologous periplasmic binding proteins