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

Direct Measurement of the Visible to UV Photodissociation Processes for the PhotoCORM TryptoCORM

PhotoCORMs are light‐triggered compounds that release CO for medical applications. Here, we apply laser spectroscopy in the gas phase to TryptoCORM, a known photoCORM that has been shown to destroy Escherichia coli upon visible‐light activation. Our experiments allow us to map TryptoCORM’s photochemistry across a wide wavelength range by using novel laser‐interfaced mass spectrometry (LIMS). LIMS provides the intrinsic absorption spectrum of the photoCORM along with the production spectra of all of its ionic photoproducts for the first time. Importantly, the photoproduct spectra directly reveal the optimum wavelengths for maximizing CO ejection, and the extent to which CO ejection is compromised at redder wavelengths. A series of comparative studies were performed on TryptoCORM‐CH3CN which exists in dynamic equilibrium with TryptoCORM in solution. Our measurements allow us to conclude that the presence of the labile CH3CN facilitates CO release over a wider wavelength range. This work demonstrates the potential of LIMS as a new methodology for assessing active agent release ( e.g. CO, NO, H2S) from light‐activated prodrugs

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

Understanding Precatalyst Activation and Speciation in Manganese-Catalyzed C-H Bond Functionalization Reactions

An investigation into species formed following precatalyst activation in Mn-catalyzed C-H bond functionalization reactions is reported. Time-resolved infrared spectroscopy demonstrates that light-induced CO dissociation from precatalysts [Mn(C^N)(CO)4] (C^N = cyclometalated 2-phenylpyridine (1a), cyclometalated 1,1-bis(4-methoxyphenyl)methanimine (1b)) in a toluene solution of 2-phenylpyridine (2a) or 1,1-bis(4-methoxyphenyl)methanimine (2b) results in the initial formation of solvent complexes fac-[Mn(C^N)(CO)3(toluene)]. Subsequent solvent substitution on a nanosecond time scale then yields fac-[Mn(C^N)(CO)3(κ1-(N)-2a)] and fac-[Mn(C^N)(CO)3(κ1-(N)-2b)], respectively. When the experiments are performed in the presence of phenylacetylene, the initial formation of fac-[Mn(C^N)(CO)3(toluene)] is followed by a competitive substitution reaction to give fac-[Mn(C^N)(CO)3(2)] and fac-[Mn(C^N)(CO)3(η2-PhC2H)]. The fate of the reaction mixture depends on the nature of the nitrogen-containing substrate used. In the case of 2-phenylpyridine, migratory insertion of the alkyne into the Mn-C bond occurs, and fac-[Mn(C^N)(CO)3(κ1-(N)-2a)] remains unchanged. In contrast, when 2b is used, substitution of the η2-bound phenylacetylene by 2b occurs on a microsecond time scale, and fac-[Mn(C^N)(CO)3(κ1-(N)-2b)] is the sole product from the reaction. Calculations with density functional theory indicate that this difference in behavior may be correlated with the different affinities of 2a and 2b for the manganese. This study therefore demonstrates that speciation immediately following precatalyst activation is a kinetically controlled event. The most dominant species in the reaction mixture (the solvent) initially binds to the metal. The subsequent substitution of the metal-bound solvent is also kinetically controlled (on a ns time scale) prior to the thermodynamic distribution of products being obtained

The antimicrobial activity of a carbon monoxide releasing molecule (EBOR-CORM-1) is shaped by intraspecific variation within3 Pseudomonas aeruginosa populations

Carbon monoxide releasing molecules (CORMs) have been suggested as a new synthetic class of antimicrobials to treat bacterial infections. Here we utilized a novel EBOR-CORM-1 ([NEt4][MnBr2(CO)4]) capable of water-triggered CO-release, and tested its efficacy against a collection of clinical Pseudomonas aeruginosa strains that differ in infection-related virulence traits. We found that while EBOR-CORM-1 was effective in clearing planktonic and biofilm cells of P. aeruginosa strain PAO1 in a concentration dependent manner, this effect was less clear and varied considerably between different P. aeruginosa cystic fibrosis (CF) lung isolates. While a reduction in cell growth was observed after 8 h of CORM application, either no effect or even a slight increase in cell densities and the amount of biofilm was observed after 24 h. This variation could be partly explained by differences in bacterial virulence traits: while CF isolates showed attenuated in vivo virulence and growth compared to strain PAO1, they formed much more biofilm, which could have potentially protected them from the CORM. Even though no clear therapeutic benefits against a subset of isolates was observed in an in vivo wax moth acute infection model, EBOR-CORM-1 was more efficient at reducing the growth of CF isolate co-culture populations harboring intraspecific variation, in comparison with efficacy against more uniform single isolate culture populations. Together these results suggest that CORMs could be effective at controlling genetically diverse P. aeruginosa populations typical for natural chronic CF infections and that the potential benefits of some antibiotics might not be observed if tested only against clonal bacterial populations

A comprehensive understanding of carbon-carbon bond formation by alkyne migratory insertion into manganacycles

Migratory insertion (MI) is one of the most important processes underpinning the transition metal-catalysed formation of C-C and C-X bonds. In this work, a comprehensive model of MI is presented, based on the direct observation of the states involved in the coupling of alkynes with cyclometallated ligands, augmented with insight from computational chemistry. Time-resolved spectroscopy demonstrates that photolysis of complexes [Mn(C^N)(CO)4] (C^N = cyclometalated ligand) results in ultra-fast dissociation of a CO ligand. Performing the experiment in a toluene solution of an alkyne results in the initial formation of a solvent complex fac-[Mn(C^N)(toluene)(CO)3]. Solvent substitution gives an η2-alkyne complex fac-[Mn(C^N)(η2-R1C2R2)(CO)3] which undergoes MI of the unsaturated ligand into the Mn-C bond. These data allowed for the dependence of second order rate constants for solvent substitution and first order rate constants for C-C bond formation to be determined. A systematic investigation into the influence of the alkyne and C^N ligand on this process is reported. The experimental data enabled the development of a computational model for the MI reaction which demonstrated that a synergic interaction between the metal and the nascent C-C bond controls both the rate and regiochemical outcome of the reaction. The time-resolved spectroscopic method enabled the observation of a multi-step reaction occurring over 8 orders of magnitude in time, including the formation of solvent complexes, ligand substitution and two sequential C-C bond formation steps

Coumarin C−H Functionalization by Mn(I) Carbonyls : Mechanistic Insight by Ultra-Fast IR Spectroscopic Analysis

Mn(I) C−H functionalization of coumarins provides a versatile and practical method for the rapid assembly of fused polycyclic pyridinium-containing coumarins in a regioselective manner. The synthetic strategy enables application of bench-stable organomanganese reagents in both photochemical- and thermal-promoted reactions. The cyclomanganated intermediates, and global reaction system, provide an ideal testing ground for structural characterization of the active Mn(I) carbonyl-containing species, including transient species observable by ultra-fast time-resolved spectroscopic methods. The thermodynamic reductive elimination product, solely encountered from reaction between alkynes and air-stable organometallic cyclomanganated coumarins, has enabled characterization of a critical seven-membered Mn(I) intermediate, detected by time-resolved infrared spectroscopy, enabling the elucidation of the temporal profile of key steps in the reductive elimination pathway. Quantitative data are provided. Manganated polycyclic products are readily decomplexed by AgBF4, opening-up an efficient route to the formation of π-extended hybrid coumarin-pyridinium compounds

Childhood characteristics and participation in Scottish Mental Survey 1947 6-Day Sample Follow-ups: Implications for participation in aging studies

Given the ‘graying’ of especially the populations of most western nations, studies of factors contributing to well-being in later life are important and common, and it is important to their accuracy that they be based on samples representative of the populations in the relevant age groups. There is general awareness that several characteristics such as sex, socioeconomic status, cognitive ability and personality are associated with study participation, but many researchers assume that this reflects life circumstances at time of recruitment rather than inherent individual characteristics that shape those circumstances throughout people’s lives. The Scottish Mental Survey 1947 6-Day Sample Follow-Up Study offered an unusual opportunity to test this assumption, as follow-up study participation data were available both in young adulthood and at age 77. Participation at age 77 was dramatically restricted relative to that in young adulthood. Cognitive abilities and a composite of conscientiousness-related variables independent of cognitive ability assessed in childhood predicted participation at young ages, but much more strongly at older ages. Evidence was available that these results were not specific to the recruiting and assessment methods used in this study. This suggests that participation in studies of aging is a function not just of contemporaneous circumstances but also of early-life cognitive and personality characteristics that have shaped those circumstances.

A global alliance declaring war on cassava viruses in Africa

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