Electrochemical and solution structural characterisation of Fe(III) azotochelin complexes : Examining the coordination behaviour of a tetradentate siderophore

We report an electrochemical setup comprising a boron-doped diamond (BDD) working electrode for the electrochemical study of iron(III) catecholate siderophores. We demonstrate its successful application in the voltammetric investigation of iron(III) azotochelin, an iron complex of a bis(catecholate) siderophore. Cyclic voltammetry results, when complemented by UV-vis and native ESI-MS characterisation reveal the formation of a coordinatively-unsaturated tetracoordinate 1:1 complex of Fe:azotochelin (M1:L1) at neutral pH, contrary to iron(III) tetradentate siderophore complexes of other classes which favour the hexacoordinate environment of a M2:L3 species. A notable effect of pH and buffer composition on the reduction potential of iron(III) azotochelin is demonstrated. Lower pH values and buffers encompassing primary or secondary amines facilitate a positive potential shift of up to +290 mV and +250 mV vs Ag/AgCl 3M NaCl, respectively. The study was extended to the investigation of the iron(III) complexes of hexadentate siderophores. For tris(catecholate) siderophores, enterobactin and protochelin, the reduction potentials were found to lie beyond the potential window accessible to the BDD electrode, however, we were successful in observing the electrochemical behaviour of a tris(hydroxamate) siderophore, ferricrocin

Carbon nitride as a ligand: edge-site coordination of ReCl(CO)3-fragments to g-C3 N4

IR spectroscopy and model structural studies show binding of ReCl(CO) 3-fragments to carbon nitride (g-C 3N 4) occurs via κ 2 N,N′ bidentate coordination

Light-Induced Activation of a Molybdenum Oxotransferase Model within a Ru(II)-Mo(VI) Dyad

Nature uses molybdenum-containing enzymes to catalyze oxygen atom transfer (OAT) from water to organic substrates. In these enzymes, the two electrons that are released during the reaction are rapidly removed, one at a time, by spatially separated electron transfer units. Inspired by this design, a Ru(II)-Mo(VI) dyad was synthesized and characterized, with the aim of accelerating the rate-determining step in the cis-dioxo molybdenum-catalyzed OAT cycle, the transfer of an oxo ligand to triphenyl phosphine, via a photo-oxidation process. The dyad consists of a photoactive bis(bipyridyl)-phenanthroline ruthenium moiety that is covalently linked to a bioinspired cis-dioxo molybdenum thiosemicarbazone complex. The quantum yield and luminescence lifetimes of the dyad [Ru(bpy)2(L(2))MoO2(solv)](2+) were determined. The major component of the luminescence decay in MeCN solution (τ = 1149 ± 2 ns, 67%) corresponds closely to the lifetime of excited [Ru(bpy)2(phen-NH2)](2+), while the minor component (τ = 320 ± 1 ns, 31%) matches that of [Ru(bpy)2(H2-L(2))](2+). In addition, the (spectro)electrochemical properties of the system were investigated. Catalytic tests showed that the dyad-catalyzed OAT from dimethyl sulfoxide to triphenyl phosphine proceeds significantly faster upon irradiation with visible light than in the dark. Methylviologen acts as a mediator in the photoredox cycle, but it is regenerated and hence only required in stoichiometric amounts with respect to the catalyst rather than sacrificial amounts. It is proposed that oxidative quenching of the photoexcited Ru unit, followed by intramolecular electron transfer, leads to the production of a reactive one-electron oxidized catalyst, which is not accessible by electrochemical methods. A significant, but less pronounced, rate enhancement was observed when an analogous bimolecular system was tested, indicating that intramolecular electron transfer between the photosensitizer and the catalytic center is more efficient than intermolecular electron transfer between the separate components

Synthesis and antimicrobial activity of an SO2-releasing siderophore conjugate

A novel Trojan Horse conjugate consisting of an SO2-releasing 2,4-dinitrobenzenesulfonamide group attached to the monocatecholate siderophore aminochelin was synthesized to examine whether a bidentate catecholate siderophore unit could help potentiate the antimicrobial activity of SO2-releasing prodrugs. The conjugate obtained displays rapid SO2 release on reaction with glutathione, and proved more active against S. aureus than a comparable SO2-releasing prodrug lacking the siderophore unit, although activity required micromolar concentrations. The conjugate was inactive against wild-type E. coli, but activity was observed against an entA mutant strain that is unable to produce its major siderophores. Hence, the poor activity of the conjugate in wild-type E. coli may be due to the production of native siderophores that can compete with the conjugate for iron binding and uptake

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

Synthesis and biochemical evaluation of cephalosporin analogues equipped with chemical tethers

Molecular probes typically require structural modifications to allow for the immobilisation or bioconjugation with a desired substrate but the effects of these changes are often not evaluated. Here, we set out to determine the effects of attaching functional handles to a first-generation cephalosporin. A series of cephalexin derivatives was prepared, equipped with chemical tethers suitable for the site-selective conjugation of antibiotics to functionalised surfaces. The tethers were positioned remotely from the β-lactam ring to ensure minimal effect to the antibiotic's pharmacophore. Herein, the activity of the modified antibiotics was evaluated for binding to the therapeutic target, the penicillin binding proteins, and shown to maintain binding interactions. In addition, the deactivation of the modified drugs by four β-lactamases (TEM-1, CTX-M-15, AmpC, NDM-1) was investigated and the effect of the tethers on the catalytic efficiencies determined. CTX-M-15 was found to favour hydrolysis of the parent antibiotic without a tether, whereas AmpC and NDM-1 were found to favour the modified analogues. Furthermore, the antimicrobial activity of the derivatives was evaluated to investigate the effect of the structural modifications on the antimicrobial activity of the parent drug, cephalexin

Redox-reversible siderophore-based catalyst anchoring within cross-linked artificial metalloenzyme aggregates enables enantioselectivity switching

The immobilisation of artificial metalloenzymes (ArMs) holds promise for the implementation of new biocatalytic reactions. We present the synthesis of cross-linked artificial metalloenzyme aggregates (CLArMAs) with excellent recyclability, as alternative to carrier-based immobilisation strategies. Furthermore, iron-siderophore supramolecular anchoring facilitates redox-triggered cofactor release, enabling CLArMAs to be recharged with alternative cofactors for diverse selectivity

A Salmochelin S4-inspired Ciprofloxacin Trojan Horse Conjugate

A novel ciprofloxacin-siderophore Trojan Horse antimicrobial was prepared by incorporating key design features of salmochelin S4, a stealth siderophore that evades mammalian siderocalin capture via its glycosylated catechol units. As-sessment of the antimicrobial activity of the conjugate revealed that attachment of the salmochelin mimic resulted in decreased potency, compared to ciprofloxacin, against two Escherichia coli strains, K12 and Nissle 1917, in both iron-replete and deplete conditions. This observation could be attributed to a combination of reduced DNA gyrase inhibi-tion, as confirmed by in vitro DNA gyrase assays, and reduced bacterial uptake. Uptake was monitored using radio-labelling with iron-mimetic 67Ga3+, which revealed limited cellular uptake in E. coli K12. In contrast, previously reported staphyloferrin-based conjugates displayed measurable uptake in analogous 67Ga3+, labelling studies. These results suggest that in designing Trojan Horse antimicrobials, the choice of siderophore and the nature and length of the link-er remains a significant challenge

Unveiling the origin of photo-induced enhancement of oxidation catalysis at Mo(VI) centres of Ru(II)–Mo(VI) dyads

Photo-induced oxidation-enhancement in biomimetic bridged Ru(II)–Mo(VI) photo-catalyst is unexpectedly photo-activated in ps timescales. One-photon absorption generates an excited state where both photo-oxidized and photo-reduced catalytic centres are activated simultaneously and independently

Surface-Bound Antibiotic for the Detection of β-Lactamases

Antimicrobial resistance (AMR) has been identified as a major threat to public health worldwide. To ensure appropriate use of existing antibiotics, rapid and reliable tests of AMR are necessary. One of the most common and clinically important forms of bacterial resistance is to b-lactam antibiotics (e.g. penicillin). This resistance is often caused by b-lactamases, which hydrolyze b-lactam drugs, rendering them ineffective. Current methods for detecting these enzymes either require time- consuming growth assays or antibiotic mimics such as nitrocefin. Here, we report the development of a surface-bound, clinically- relevant, b-lactam drug that can be used to detect b-lactamases. Furthermore, we demonstrate the use of these functionalized surfaces to selectively detect b-lactamases in complex biological media, such as urine