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Innovative N -acridine thiosemicarbazones (NATs) were designed along with their iron(iii), copper(ii), and zinc(ii) complexes. Lysosomal targeting was promoted by specifically incorporating the lysosomotropic Pgp substrate, acridine, into the thiosemicarbazone scaffold to maintain the tridentate N, N, S-donor system. The acridine moiety enables a significant advance in thiosemicarbazone design, since: (1) it enables tracking of the drugs by confocal microscopy using its inherent fluorescence; (2) it is lysosomotropic enabling lysosomal targeting; and (3) as acridine is a P-glycoprotein (Pgp) substrate, it facilitates lysosomal targeting, resulting in the drug overcoming Pgp-mediated resistance. These new N -acridine analogues are novel, and this is the first time that acridine has been specifically added to the thiosemicarbazone framework to achieve the three important properties above. These new agents displayed markedly greater anti-proliferative activity against resistant Pgp-expressing cells than very low Pgp-expressing cells. The anti-proliferative activity of NATs against multiple Pgp-positive cancer cell-types (colon, lung, and cervical carcinoma) was abrogated by the third generation Pgp inhibitor, Elacridar, and also Pgp siRNA that down-regulated Pgp. Confocal microscopy demonstrated that low Pgp in KB31 (-Pgp) cells resulted in acridine's proclivity for DNA intercalation promoting NAT nuclear-targeting. In contrast, high Pgp in KBV1 (+Pgp) cells led to NAT lysosomal sequestration, preventing its nuclear localisation. High Pgp expression in KBV1 (+Pgp) cells resulted in co-localization of NATs with the lysosomal marker, LysoTracker™, that was significantly ( p < 0.001) greater than the positive control, the di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) Zn(ii) complex, [Zn(DpC) 2 ]. Incorporation of acridine into the thiosemicarbazone scaffold led to Pgp-mediated transport into lysosomes to overcome Pgp-resistance., Competing Interests: The authors declare no competing conflict of interest., (This journal is © The Royal Society of Chemistry.)

We implemented isosteric replacement of sulfur to selenium in a novel thiosemicarbazone (PPTP4c4mT) to create a selenosemicarbazone (PPTP4c4mSe) that demonstrates potentiated anticancer efficacy and selectivity. Their design specifically incorporated cyclohexyl and styryl moieties to sterically inhibit the approach of their Fe(III) complexes to the oxy-myoglobin heme plane. Importantly, in contrast to the Fe(III) complexes of the clinically trialed thiosemicarbazones Triapine, COTI-2, and DpC, the Fe(III) complexes of PPTP4c4mT and PPTP4c4mSe did not induce detrimental oxy-myoglobin oxidation. Furthermore, PPTP4c4mSe demonstrated more potent antiproliferative activity than the homologous thiosemicarbazone, PPTP4c4mT, with their selectivity being superior or similar, respectively, to the clinically trialed thiosemicarbazone, COTI-2. An advantageous property of the selenosemicarbazone Zn(II) complexes relative to their thiosemicarbazone analogues was their greater transmetalation to Cu(II) complexes in lysosomes. This latter effect probably promoted their antiproliferative activity. Both ligands down-regulated multiple key receptors that display inter-receptor cooperation that leads to aggressive and resistant breast cancer.

Motivated by the ambition to establish an enzyme-driven bioleaching pathway for copper extraction, properties of the Type-1 copper protein rusticyanin from Acidithiobacillus ferrooxidans (AfR) were compared with those from an ancestral form of this enzyme (N0) and an archaeal enzyme identified in Ferroplasma acidiphilum (FaR). While both N0 and FaR show redox potentials similar to that of AfR their electron transport rates were significantly slower. The lack of a correlation between the redox potentials and electron transfer rates indicates that AfR and its associated electron transfer chain evolved to specifically facilitate the efficient conversion of the energy of iron oxidation to ATP formation. In F. acidiphilum this pathway is not as efficient unless it is up-regulated by an as of yet unknown mechanism. In addition, while the electrochemical properties of AfR were consistent with previous data, previously unreported behavior was found leading to a form that is associated with a partially unfolded form of the protein. The cyclic voltammetry (CV) response of AfR immobilized onto an electrode showed limited stability, which may be connected to the presence of the partially unfolded state of this protein. Insights gained in this study may thus inform the engineering of optimized rusticyanin variants for bioleaching processes as well as enzyme-catalyzed solubilization of copper-containing ores such as chalcopyrite., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Subjecting the Australian marine-derived fungus Aspergillus noonimiae CMB-M0339 to cultivation profiling using an innovative miniaturized 24-well plate format (MATRIX) enabled access to new examples of the rare class of 2,6-diketopiperazines, noonazines A-C ( 1 - 3 ), along with the known analogue coelomycin ( 4 ), as well as a new azaphilone, noonaphilone A ( 5 ). Structures were assigned to 1 - 5 on the basis of a detailed spectroscopic analysis, and in the case of 1 - 2 , an X-ray crystallographic analysis. Plausible biosynthetic pathways are proposed for 1 - 4 , involving oxidative Schiff base coupling/dimerization of a putative Phe precursor. Of note, 2 incorporates a rare meta -Tyr motif, typically only reported in a limited array of Streptomyces metabolites. Similarly, a plausible biosynthetic pathway is proposed for 5 , highlighting a single point for stereo-divergence that allows for the biosynthesis of alternate antipodes, for example, the 7 R noonaphilone A ( 5 ) versus the 7 S deflectin 1a ( 6 ).

A chemical investigation of Australian soil-derived bacteria Actinomadura sp. S4S-00069B08 yielded eight new benzenoid ansamycins, goondansamycins A-H. Goondansamycins feature rare 1,4-benzoxazin-3-one or o -diamino- p -benzoquinone moieties and can exist as both aglycones or 9- O -α-glycosides of either d-rhodinose or d-amicetose. Structures were solved on the basis of detailed spectroscopy, including X-ray analysis.

This study investigates the influence of ligand charge on transition energies in a series of CuN 2 S 2 complexes based on dithiocarbazate Schiff base ligands using Cu K-edge X-ray absorption spectroscopy (XAS) and Kβ valence-to-core (VtC) X-ray emission spectroscopy (XES). By comparing the formally Cu(II) complexes [CuII(HL1)] (HL1 2- = dimethyl pentane-2,4-diylidenebis[carbonodithiohydrazonate]) and [CuII(HL2)] (HL2 2- = dibenzyl pentane-2,4-diylidenebis[carbonodithiohydrazonate]) and the formally Cu(III) complex [CuIII(L2)], distinct changes in transition energies are observed, primarily attributed to the metal oxidation state. Density functional theory (DFT) calculations demonstrate how an increased negative charge on the deprotonated L2 3- ligand stabilizes the Cu(III) center through enhanced charge donation, modulating the core transition energies. Overall, significant shifts to higher energies are noted upon metal oxidation, emphasizing the importance of scrutinizing ligand structure in XAS/VtC XES analysis. The data further support the redox-innocent role of the Schiff base ligands and underscore the criticality of ligand protonation levels in future spectroscopic studies, particularly for catalytic intermediates. The combined XAS-VtC XES methodology validates the Cu(III) oxidation state assignment while offering insights into ligand protonation effects on core-level spectroscopic transitions.

Oxidised derivatives of cholesterol have been shown to inhibit the growth of Mycobacterium tuberculosis (Mtb). The bacteriostatic activity of these compounds has been attributed to their inhibition of CYP125A1 and CYP142A1, two metabolically critical cytochromes P450 that initiate degradation of the sterol side chain. Here, we synthesise and characterise an extensive library of 28 cholesterol derivatives to develop a structure-activity relationship for this class of inhibitors. The candidate compounds were evaluated for MIC with virulent Mtb and in binding studies with CYP125A1 and CYP142A1 from Mtb., (Copyright © 2024. Published by Elsevier Ltd.)

The first synthesis of the 5-aza[1.0]triblattane skeleton was achieved through a [4 + 2] cycloaddition approach using a suitably protected azetine and cyclopentadiene. A series of azetines were synthesized to explore both stability and suitable N-protection. The key step following cycloaddition utilized a noninitiated protonated aminyl radical cyclization to install the final 5-azatriblattane bond, but it was found to be considerably more unstable than the 6-aza isomer under acidic conditions.

Copper-catalyzed electrochemical atom transfer radical addition ( e ATRA) is a new method for the creation of new C-C bonds under mild conditions. In this work, we have explored the reactivity of an analogous series of N 4 macrocyclic Cu II complexes as e ATRA precatalysts, which are primed by reduction to their monovalent oxidation state. These complexes were fully characterized structurally, spectroscopically, and electrochemically. A spectrum of radical activation reactivity was found across the series [Cu I (Me 4 cyclen)(NCMe)] + (Me 4 cyclen = 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane), [Cu I (Me 4 cyclam)(NCMe)] + (Me 4 cyclam = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), and [Cu I (Me 2 py 2 clen)(NCMe)] + (Me 2 py 2 clen = 3,7-dimethyl-3,7-diaza-1,5(2,6)-dipyridinacyclo-octaphane). The rate of radical production by [Cu(Me 2 py 2 clen)(NCMe)] + was modest, but rapid radical capture to form the organocopper complex [Cu I (Me 2 py 2 clen)(CH 2 CN)] led to a dramatic acceleration in catalysis, greater than seen in any comparable Cu complex, but this led to rapid radical self-termination instead of radical addition.

Homocubane, a highly strained cage hydrocarbon, contains two very different positions for the introduction of a nitrogen atom into the skeleton, e. g., a position 1 exchange results in a tertiary amine whereas position 9 yields a secondary amine. Herein reported is the synthesis of 9-azahomocubane along with associated structural characterization, physical property analysis and chemical reactivity. Not only is 9-azahomocubane readily synthesized, and found to be stable as predicted, the basicity of the secondary amine was observed to be significantly lower than the structurally related azabicyclo[2.2.1]heptane, although similar to 1-azahomocubane., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The di-2-pyridylthiosemicarbazone (DpT) analogs demonstrate potent and selective anti-proliferative activity against human tumors. The current investigation reports the synthesis and chemical and biological characterization of the Fe(iii), Co(iii), Ni(ii), Cu(ii), Zn(ii), Ga(iii), and Pd(ii) complexes of the promising second generation DpT analog, di-2-pyridylketone-4-ethyl-4-methyl-3-thiosemicarbazone (Dp4e4mT). These studies demonstrate that the Dp4e4mT Co(iii), Ni(ii), and Pd(ii) complexes display distinct biological activity versus those with Cu(ii), Zn(ii), and Ga(iii) regarding anti-proliferative efficacy against cancer cells and a detrimental off-target effect involving oxidation of oxy-myoglobin (oxy-Mb) and oxy-hemoglobin (oxy-Hb). With regards to anti-proliferative activity, the Zn(ii) and Ga(iii) Dp4e4mT complexes demonstrate facile transmetallation with Cu(ii), resulting in efficacy against tumor cells that is strikingly similar to the Dp4e4mT Cu(ii) complex (IC 50 : 0.003-0.006 μM and 72 h). Relative to the Zn(ii) and Ga(iii) Dp4e4mT complexes, the Dp4e4mT Ni(ii) complex demonstrates kinetically slow transmetallation with Cu(ii) and intermediate anti-proliferative effects (IC 50 : 0.018-0.076 μM after 72 h). In contrast, the Co(iii) and Pd(ii) complexes demonstrate poor anti-proliferative activity (IC 50 : 0.262-1.570 μM after 72 h), probably due to a lack of transmetallation with Cu(ii). The poor efficacy of the Dp4e4mT Co(iii), Ni(ii), and Pd(ii) complexes to transmetallate with Fe(iii) markedly suppresses the oxidation of oxy-Mb and oxy-Hb. In contrast, the 2 : 1 Dp4e4mT: Cu(ii), Zn(ii), and Ga(iii) complexes demonstrate facile reactions with Fe(iii), leading to the redox active Dp4e4mT Fe(iii) complex and oxy-Mb and oxy-Hb oxidation. This study demonstrates the key role of differential transmetallation of Dp4e4mT complexes that has therapeutic ramifications for their use as anti-cancer agents., Competing Interests: No financial conflict of interest exists., (This journal is © The Royal Society of Chemistry.)

The oxygen-tolerant and molybdenum-dependent formate dehydrogenase FdsDABG from Cupriavidus necator is capable of catalyzing both formate oxidation to CO 2 and the reverse reaction (CO 2 reduction to formate) at neutral pH, which are both reactions of great importance to energy production and carbon capture. FdsDABG is replete with redox cofactors comprising seven Fe/S clusters, flavin mononucleotide, and a molybdenum ion coordinated by two pyranopterin dithiolene ligands. The redox potentials of these centers are described herein and assigned to specific cofactors using combinations of potential-dependent continuous wave and pulse EPR spectroscopy and UV/visible spectroelectrochemistry on both the FdsDABG holoenzyme and the FdsBG subcomplex. These data represent the first redox characterization of a complex metal dependent formate dehydrogenase and provide an understanding of the highly efficient catalytic formate oxidation and CO 2 reduction activity that are associated with the enzyme.

The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe(III), Cu(II), and Zn(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC 50 : 0.009-0.066 μM), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe(III) complexes to the heme plane and its oxidation. The 1:1 Cu(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation.

The bacterial molybdenum (Mo)-containing formate dehydrogenase (FdsDABG) from Cupriavidus necator is a soluble NAD + -dependent enzyme belonging to the DMSO reductase family. The holoenzyme is complex and possesses nine redox-active cofactors including a bis(molybdopterin guanine dinucleotide) (bis-MGD) active site, seven iron-sulfur clusters, and 1 equiv of flavin mononucleotide (FMN). FdsDABG catalyzes the two-electron oxidation of HCOO - (formate) to CO 2 and reversibly reduces CO 2 to HCOO - under physiological conditions close to its thermodynamic redox potential. Here we develop an electrocatalytically active formate oxidation/CO 2 reduction system by immobilizing FdsDABG on a glassy carbon electrode in the presence of coadsorbents such as chitosan and glutaraldehyde. The reversible enzymatic interconversion between HCOO - and CO 2 by FdsDABG has been realized with cyclic voltammetry using a range of artificial electron transfer mediators, with methylene blue (MB) and phenazine methosulfate (PMS) being particularly effective as electron acceptors for FdsDABG in formate oxidation. Methyl viologen (MV) acts as both an electron acceptor (MV 2+ ) in formate oxidation and an electron donor (MV +• ) for CO 2 reduction. The catalytic voltammetry was reproduced by electrochemical simulation across a range of sweep rates and concentrations of formate and mediators to provide new insights into the kinetics of the FdsDABG catalytic mechanism.

The utility and scope of Cu-catalyzed halogen atom transfer chemistry have been exploited in the fields of atom transfer radical polymerization and atom transfer radical addition, where the metal plays a key role in radical formation and minimizing unwanted side reactions. We have shown that electrochemistry can be employed to modulate the reactivity of the Cu catalyst between its active (Cu I ) and dormant (Cu II ) states in a variety of ligand systems. In this work, a macrocyclic pyridinophane ligand (L1) was utilized, which can break the C-Br bond of BrCH 2 CN to release • CH 2 CN radicals when in complex with Cu I . Moreover, the [Cu I (L1)] + complex can capture the • CH 2 CN radical to form a new species [Cu II (L1)(CH 2 CN)] + in situ that, on reduction, exhibits halogen atom transfer reactivity 3 orders of magnitude greater than its parent complex [Cu I (L1)] + . This unprecedented rate acceleration has been identified by electrochemistry, successfully reproduced by simulation, and exploited in a Cu-catalyzed bulk electrosynthesis where [Cu II (L1)(CH 2 CN)] + participates as a radical donor in the atom transfer radical addition of BrCH 2 CN to a selection of styrenes. The formation of these turbocharged catalysts in situ during electrosynthesis offers a new approach to the Cu-catalyzed organic reaction methodology.

seco -1-Azacubane-2-carboxylic acid, an unusual and sterically constrained amino acid, was found to undergo amide bond formation at both the N- and C-termini using proline based bioactive molecule templates as a concept platform.

In contrast to their molybdenum dependent relatives, tungsten enzymes operate at significantly lower redox potentials, and in some cases they can carry out reversible redox transformations of their substrates and products. Still, the electrochemical properties of W enzymes have received much less attention than their Mo relatives. Herein we analyse the tungsten enzyme aldehyde oxidoreductase (AOR) from the mesophilic bacterium Aromatoleum aromaticum which has been immobilised on a glassy carbon working electrode. This generates a functional system that electrochemically oxidises a wide variety of aromatic and aliphatic aldehydes in the presence of the electron transfer mediators benzyl viologen, methylene blue or dichlorophenol indophenol. Simulation of the cyclic voltammetry has enabled a thorough kinetic analysis of the system, which reveals that methylene blue acts as a two-electron acceptor. In contrast, the other two mediators act as single electron oxidants. The different electrochemical driving forces imparted by these mediators also lead to significantly different outer sphere electron transfer rates with AOR. This work shows that electrocatalytic aldehyde oxidation can be achieved at a low applied electrochemical potential leading to an extremely energy efficient catalytic process., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Organocopper(II) reagents are an unexplored frontier of copper catalysis. Despite being proposed as reactive intermediates, an understanding of the stability and reactivity of the Cu II -C bond has remained elusive. Two main pathways can be considered for the cleavage mode of a Cu II -C bond: homolysis and heterolysis. We recently showed how organocopper(II) reagents can react with alkenes via radical addition, a homolytic pathway. In this work, the decomposition of the complex [Cu II LR] + [L = tris(2- dimethylaminoethyl)amine, Me 6 tren, R = NCCH 2 - ] in the absence and presence of an initiator (RX, X = Cl, Br) was evaluated. When no initiator was present, first-order Cu II -C bond homolysis occurred producing [Cu I L] + and succinonitrile, via radical termination. When an excess of the initiator was present, a subsequent formation of [Cu II LX] + via a second-order reaction was found, which results from the reaction of [Cu I L] + with RX following homolysis. However, when Brønsted acids (R'-OH: R' = H, Me, Ph, PhCO) were present, heterolytic cleavage of the Cu II -C bond produced [Cu II L(OR')] + and MeCN. Kinetic studies were undertaken to obtain the thermal (Δ H ⧧ , Δ S ⧧ ) and pressure (Δ V ⧧ ) activation parameters and deuterium kinetic isotopic effects, which provided an understanding of the strength of the Cu II -C bond and the nature of the transition state for the reactions involved. These results reveal possible reaction pathways for organocopper(II) complexes relevant to their applications as catalysts in C-C bond forming reactions.

Highly strained cage hydrocarbons have long stood as fundamental molecules to explore the limits of chemical stability and reactivity, probe physical properties, and more recently as bioactive molecules and in materials discovery. Interestingly, the nitrogenous congeners have attracted much less attention. Previously absent from the literature, azahomocubanes, offer an opportunity to investigate the effects of a nitrogen atom when incorporated into a highly constrained polycyclic environment. Herein disclosed is the synthesis of 1-azahomocubane, accompanied by comprehensive structural characterization, physical property analysis and chemical reactivity. These data support the conclusion that nitrogen is remarkably well tolerated in a highly strained environment., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

1-Azasugar analogues of l-iduronic acid (l-IdoA) and d-glucuronic acid (d-GlcA) and their corresponding enantiomers have been synthesized as potential pharmacological chaperones for mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by mutations in the gene encoding α-iduronidase (IDUA). The compounds were efficiently synthesized in nine or ten steps from d- or l-arabinose, and the structures were confirmed by X-ray crystallographic analysis of key intermediates. All compounds were inactive against IDUA, although l-IdoA-configured 8 moderately inhibited β-glucuronidase (β-GLU). The d-GlcA-configured 9 was a potent inhibitor of β-GLU and a moderate inhibitor of the endo-β-glucuronidase heparanase. Co-crystallization of 9 with heparanase revealed that the endocyclic nitrogen of 9 forms close interactions with both the catalytic acid and catalytic nucleophile., (© 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Enzyme-catalyzed reaction cascades play an increasingly important role for the sustainable manufacture of diverse chemicals from renewable feedstocks. For instance, dehydratases from the ilvD/EDD superfamily have been embedded into a cascade to convert glucose via pyruvate to isobutanol, a platform chemical for the production of aviation fuels and other valuable materials. These dehydratases depend on the presence of both a Fe-S cluster and a divalent metal ion for their function. However, they also represent the rate-limiting step in the cascade. Here, catalytic parameters and the crystal structure of the dehydratase from Paralcaligenes ureilyticus (PuDHT, both in presence of Mg 2+ and Mn 2+ ) were investigated. Rate measurements demonstrate that the presence of stoichiometric concentrations Mn 2+ promotes higher activity than Mg 2+ , but at high concentrations the former inhibits the activity of PuDHT. Molecular dynamics simulations identify the position of a second binding site for the divalent metal ion. Only binding of Mn 2+ (not Mg 2+ ) to this site affects the ligand environment of the catalytically essential divalent metal binding site, thus providing insight into an inhibitory mechanism of Mn 2+ at higher concentrations. Furthermore, in silico docking identified residues that play a role in determining substrate binding and selectivity. The combined data inform engineering approaches to design an optimal dehydratase for the cascade., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

In this work, the Na 3 [Ln(ODA) 3 ]·2NaClO 4 ·6H 2 O (Ln = Ce-Yb; ODA = oxydiacetate) series was analyzed with the ab initio ligand field theory (AILFT) module of the ORCA computational suite. The results were discussed within the framework of the angular overlap model (AOM) and compared to literature data. We find that the structural changes observed across the series exemplifies the effects of the lanthanide contraction also manifesting in the value of the AOM parameters. It is also shown that the complete active space self-consistent field (CASSCF) methodology is sufficient to describe the ligand field interactions in mononuclear lanthanide complexes, and the effects of dynamic correlation, through n -electron valence state perturbation theory (NEVPT2), are discussed. The calculated ligand field parameters of the present work are compared to the experimentally derived values from the literature.

A novel, potent, and selective antitumor agent, namely ( E )-3-phenyl-1-(2-pyridinyl)-2-propen-1-one 4,4-dimethyl-3-thiosemicarbazone (PPP44mT), and its analogues were synthesized and characterized and displayed strikingly distinctive properties. This activity was mediated by the inclusion of a styrene moiety, which through steric and electrochemical mechanisms prevented deleterious oxy-myoglobin or oxy-hemoglobin oxidation relative to other potent thiosemicarbazones, i.e., di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) or di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT). Structure-activity relationship analysis demonstrated specific tuning of PPP44mT electrochemistry further inhibited oxy-myoglobin or oxy-hemoglobin oxidation. Both PPP44mT and its Cu(II) complexes showed conspicuous almost immediate cytotoxicity against SK-N-MC tumor cells (within 3 h). In contrast, [Zn(PPP44mT) 2 ] demonstrated a pronounced delay in activity, taking 48 h before marked antiproliferative efficacy was apparent. As such, [Zn(PPP44mT) 2 ] was designated as a "stealth Zn(II) complex" that overcomes the near immediate cytotoxicity of PPP44mT or its copper complexes. Upon examination of the suppression of oncogenic signaling, [Zn(PPP44mT) 2 ] was superior at inhibiting cyclin D1 expression compared to DpC or Dp44mT.

The rhodium(II)-catalyzed reaction of a model alkenyl donor/acceptor N -sulfonyltriazole with a wide selection of furans is reported. This investigation unearthed a range of structurally diverse carbocyclic and ring-opened products, in good to excellent yields. The products obtained are proposed to arise selectively via cyclopropanation or zwitterionic rearrangement pathways, which are highly dependent on both the structural and electronic features of the furan substrate.

This study showcases the application of an integrated workflow of molecular networking chemical profiling (GNPS), together with miniaturized microbioreactor cultivation profiling (MATRIX) to successfully detect, dereplicate, prioritize, optimize the production, isolate, characterize, and identify a diverse selection of new chemically labile natural products from the Queensland sheep pasture soil-derived fungus Aspergillus sp. CMB-MRF324. More specifically, we report the new tryptamine enamino tripeptide aspergillamides E-F ( 7 - 8 ), dihydroquinoline-2-one aflaquinolones H-I ( 11 - 12 ), and prenylated phenylbutyrolactone aspulvinone Y ( 14 ), along with an array of known co-metabolites, including asterriquinones SU5228 ( 9 ) and CT5 ( 10 ), terrecyclic acid A ( 13 ), and aspulvinones N-CR ( 15 ), B ( 16 ), D ( 17 ), and H ( 18 ). Structure elucidation was achieved by a combination of detailed spectroscopic and chemical analysis, biosynthetic considerations, and in the case of 11, an X-ray crystallographic analysis., Competing Interests: The authors declare that they have no conflict of interest.

Analytical scale chemical/cultivation profiling prioritized the Australian marine-derived fungus Aspergillus noonimiae CMB-M0339. Subsequent investigation permitted isolation of noonindoles A-F ( 5 - 10 ) and detection of eight minor analogues ( i - viii ) as new examples of a rare class of indole diterpene (IDT) amino acid conjugate, indicative of an acyl amino acid transferase capable of incorporating a diverse range of amino acid residues. Structures for 5 - 10 were assigned by detailed spectroscopic and X-ray crystallographic analysis. The metabolites 5-14 exhibited no antibacterial properties against G-ve and G+ve bacteria or the fungus Candida albicans , with the exception of 5 which exhibited moderate antifungal activity., Competing Interests: The authors declare no conflict of interest.

Tuberculosis and parasitic infections continue to impose a significant threat to global public health and economic growth. There is an urgent need to develop new treatments to combat these diseases. Here, we report the in vitro and in vivo profiles of a new bicyclic nitroimidazole subclass, namely, nitroimidazopyrazinones, against mycobacteria and Trypanosoma cruzi . Derivatives with monocyclic side chains were selective against Mycobacterium tuberculosis and were able to reduce the bacterial load when dosed orally in mice. We demonstrated that deazaflavin-dependent nitroreductase (Ddn) could act effectively on nitroimidazopyrazinones, indicating the potential of Ddn as an activating enzyme for these new compounds in M. tuberculosis . Oral administration of compounds with extended biaryl side chains ( 73 and 74 ) was effective in suppressing infection in an acute T. cruzi -infected murine model. These findings demonstrate that active nitroimidazopyrazinones have potential to be developed as orally available clinical candidates against both tuberculosis and Chagas disease.

Molybdenum-dependent enzymes that can reduce N-hydroxylated substrates (e.g. N-hydroxyl-purines, amidoximes) are found in bacteria, plants and vertebrates. They are involved in the conversion of a wide range of N-hydroxylated organic compounds into their corresponding amines, and utilize various redox proteins (cytochrome b 5 , cyt b 5 reductase, flavin reductase) to deliver reducing equivalents to the catalytic centre. Here we present catalytic electrochemistry of the bacterial enzyme YcbX from Escherichia coli utilizing the synthetic electron transfer mediator methyl viologen (MV 2+ ). The electrochemically reduced form (MV +. ) acts as an effective electron donor for YcbX. To immobilize YcbX on a glassy carbon electrode, a facile protein crosslinking approach was used with the crosslinker glutaraldehyde (GTA). The YcbX-modified electrode showed a catalytic response for the reduction of a broad range of N-hydroxylated substrates. The catalytic activity of YcbX was examined at different pH values exhibiting an optimum at pH 7.5 and a bell-shaped pH profile with deactivation through deprotonation (pK a1 9.1) or protonation (pK a2 6.1). Electrochemical simulation was employed to obtain new biochemical data for YcbX, in its reaction with methyl viologen and the organic substrates 6-N-hydroxylaminopurine (6-HAP) and benzamidoxime (BA)., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Organocopper(ii) complexes are a rarity while organocopper(i) complexes are commonplace in chemical synthesis. In the course of building a strategy to generate organocopper(ii) species utilizing electrochemistry, a method to form compounds with Cu II -C bonds was discovered, that demonstrated remarkably potent reactivity towards different functionalized alkenes under catalytic control. The role of the organocopper(ii) complex is to act as a source of masked radicals (in this case ˙CH 2 CN) that react with an alkene to generate the corresponding γ-halonitrile in good yields through atom transfer radical addition (ATRA) to various alkenes. The organocopper(ii) complexes can be continuously regenerated electrochemically for ATRA ( e ATRA), which proceeds at room temperature, under low Cu loadings (1-10 mol%) and with the possibility of Cu-catalyst recovery., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

There is an urgent global need for the development of novel therapeutics to combat the rise of various antibiotic-resistant superbugs. Enzymes of the branched-chain amino acid (BCAA) biosynthesis pathway are an attractive target for novel anti-microbial drug development. Dihydroxy-acid dehydratase (DHAD) is the third enzyme in the BCAA biosynthesis pathway. It relies on an Fe-S cluster for catalytic activity and has recently also gained attention as a catalyst in cell-free enzyme cascades. Two types of Fe-S clusters have been identified in DHADs, i.e. [2Fe-2S] and [4Fe-4S], with the latter being more prone to degradation in the presence of oxygen. Here, we characterise two DHADs from bacterial human pathogens, Staphylococcus aureus and Campylobacter jejuni (SaDHAD and CjDHAD). Purified SaDHAD and CjDHAD are virtually inactive, but activity could be reversibly reconstituted in vitro (up to ∼19,000-fold increase with k cat as high as ∼6.7 s -1 ). Inductively-coupled plasma-optical emission spectroscopy (ICP-OES) measurements are consistent with the presence of [4Fe-4S] clusters in both enzymes. N-isopropyloxalyl hydroxamate (IpOHA) and aspterric acid are both potent inhibitors for both SaDHAD (K i =7.8 and 51.6 μM, respectively) and CjDHAD (K i =32.9 and 35.1 μM, respectively). These compounds thus present suitable starting points for the development of novel anti-microbial chemotherapeutics., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Light-induced charge separation is at the very heart of many solar harvesting technologies. The reduction of energetic barriers to charge separation and transfer increases the rate of separation and the overall efficiency of these technologies. Here we report that the internal reorganization energy of the redox acceptor, the movement of the atoms with changing charge, has a profound effect on the charge transfer rates from donor quantum dots. We experimentally studied and modelled with Marcus Theory charge transfer to cobalt complexes that have similar redox potentials covering 350 mV, but vastly different reorganization energies spanning 2 eV. While the driving force does influence the electron transfer rates, the reorganization energies had a far more profound effect, increasing charge transfer rates by several orders of magnitude. Our studies suggest that careful design of redox mediators to minimize reorganization energy is an untapped route to drastically increase the efficiency of quantum dot applications that feature charge transfer., (© 2022 Wiley-VCH GmbH.)

Human mitochondrial amidoxime reducing component 1 and 2 (mARC1 and mARC2) were immobilised on glassy carbon electrodes using the crosslinker glutaraldehyde. Voltammetry was performed in the presence of the artificial electron transfer mediator methyl viologen, whose redox potential lies negative of the enzymes' Mo VI/V and Mo V/IV redox potentials which were determined from optical spectroelectrochemical and EPR measurements. Apparent Michaelis constants obtained from catalytic limiting currents at various substrate concentrations were comparable to those previously reported in the literature from enzymatic assays. Kinetic parameters for benzamidoxime reduction were determined from cyclic voltammograms simulated using Digisim. pH dependence and stability of the enzyme electrode with time were also determined from limiting catalytic currents in saturating concentrations of benzamidoxime. The same electrode remained active after at least 9 days. Fabrication of this versatile and cost-effective biosensor is effective in screening new pharmaceutically important substrates and mARC inhibitors.

Chemical investigation of Australian pasture plant-derived Streptomyces sp. CMB-PB041, supported by miniaturized cultivation profiling and molecular network analysis, led to the isolation and characterization of 13 new macrocyclic spirotetronates, glenthmycins A-M ( 1 - 13 ), with structures assigned by detailed spectroscopic analysis, chemical degradation and derivatization, and mechanistic and biosynthetic considerations. Hydrolysis of glenthmycin B ( 2 ) yielded the aglycone 14 , whose structure and absolute configuration were secured by X-ray analysis, along with the unexpected amino sugar residues glenthose lactams A ( 15 ) and B ( 16 ), with Mosher analysis of 15 facilitating assignment of absolute configurations of the amino sugar. While the glenthmycins proved to be acid stable, treatment of isomeric glenthmycins (i.e., 3 , 6 , and 8 ) with base catalyzed rapid intramolecular trans -esterification to regio-isomeric mixtures (i.e., 3 + 6 + 8 ). Exposure of 5 to base achieved the same intramolecular trans -esterification and was instrumental in detecting and tentatively identifying two additional minor co-metabolites, glenthmycins N ( 19 ) and O ( 20 ). A structure-activity relationship analysis carried out on 1 - 13 and the semisynthetic analogues 14 and 21 - 26 revealed a promising Gram +ve antibacterial pharmacophore, effective against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), but with no detectable cytotoxicity to eukaryotic cells (i.e., fungal and human carcinoma). Of particular note, the semisynthetic analogue glenthmycin K 9-valerate ( 26 ) was unique among glenthmycins in potently inhibiting growth of the full panel of Gram +ve pathogens (IC 50 0.2-1.6 μM). We conclude with an observation that any future evaluation of the antibacterial potential of glenthmycins and related macrocyclic spirotetronates may do well to include important soil-derived Gram +ve pathogens, such as Bacillus anthrax , Clostridium botulinum , and Rhodococcus equi , the causative agents of anthrax, botulism, and livestock pneumonia.

Tetrachlorinated phthalimide analogues bearing a boron-pinacolate ester group were synthesised via two synthetic routes and evaluated in their glycosidase modulating and anticancer properties, with a view to use them in boron neutron capture therapy (BNCT), a promising radiation type for cancer, as this therapy does little damage to biological tissue. An unexpected decarbonylation/decarboxylation to five 2,3,4,5-tetrachlorobenzamides was observed and confirmed by X-ray crystallography studies, thus, giving access to a family of borylated 2,3,4,5-tetrachlorobenzamides. Biological evaluation showed the benzamide drugs to possess good to weak potencies (74.7-870 μM) in the inhibition of glycosidases, and to have good to moderate selectivity in the inhibition of a panel of 18 glycosidases. Furthermore, in the inhibition of selected glycosidases, there is a core subset of three animal glycosidases, which is always inhibited (rat intestinal maltase α-glucosidase, bovine liver β-glucosidase and β-galactosidase). This could indicate the involvement of the boron atom in the binding. These glycosidases are targeted for the management of diabetes, viral infections (via a broad-spectrum approach) and lysosomal storage disorders. Assays against cancer cell lines revealed potency in growth inhibition for three molecules, and selectivity for one of these molecules, with the growth of the normal cell line MCF10A not being affected by this compound. One of these molecules showed both potency and selectivity; thus, it is a candidate for further study in this area. This paper provides numerous novel aspects, including expedited access to borylated 2,3,4,5-tetrachlorophthalimides and to 2,3,4,5-tetrachlorobenzamides. The latter constitutes a novel family of glycosidase modulating drugs. Furthermore, a greener synthetic access to such structures is described.

Background: Iron (Fe)-induced oxidative stress leads to reactive oxygen species that damage biomembranes, with this mechanism being involved in the activity of some anti-cancer chemotherapeutics., Methods: Herein, we compared the effect of the ligand, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), or the potential ligand, Emodin, on Fe-catalyzed lipid peroxidation in cell membrane models (micelles and bicelles). These studies were performed in the presence of hydrogen peroxide (H 2 O 2 ) and the absence or presence of ascorbate., Results: In the absence of ascorbate, Fe(II)/Emodin mixtures incubated with H 2 O 2 demonstrated slight pro-oxidant properties on micelles versus Fe(II) alone, while the Fe(III)-Dp44mT complex exhibited marked antioxidant properties. Examining more physiologically relevant phospholipid-containing bicelles, the Fe(II)- and Fe(III)-Dp44mT complexes demonstrated antioxidant activity without ascorbate. Upon adding ascorbate, there was a significant increase in the peroxidation of micelles and bicelles in the presence of unchelated Fe(II) and H 2 O 2 . The addition of ascorbate to Fe(III)-Dp44mT substantially increased the peroxidation of micelles and bicelles, with the Fe(III)-Dp44mT complex being reduced by ascorbate to the Fe(II) state, explaining the increased reactivity. Electron paramagnetic resonance spectroscopy demonstrated ascorbyl radical anion generation after mixing ascorbate and Emodin, with signal intensity being enhanced by H 2 O 2 . This finding suggested Emodin semiquinone radical formation that could play a role in its reactivity via ascorbate-driven redox cycling. Examining cultured melanoma cells in vitro, ascorbate at pharmacological levels enhanced the anti-proliferative activity of Dp44mT and Emodin., Conclusions and General Significance: Ascorbate-driven redox cycling of Dp44mT and Emodin promotes their anti-proliferative activity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The Mo-dependent enzyme YiiM enzyme from Escherichia coli is a member of the sulfite oxidase family and shares many similarities with the well-studied human mitochondrial amidoxime reducing component (mARC). We have investigated YiiM catalysis using electrochemical and spectroscopic methods. EPR monitored redox potentiometry found the active site redox potentials to be Mo VI/V -0.02 V and Mo V/IV -0.12 V vs NHE at pH 7.2. In the presence of methyl viologen as an electrochemically reduced electron donor, YiiM catalysis was studied with a range of potential substrates. YiiM preferentially reduces N-hydroxylated compounds such as hydroxylamines, amidoximes, N-hydroxypurines and N-hydroxyureas but shows little or no activity against amine-oxides or sulfoxides. The pH optimum for catalysis was 7.1 and a bell-shaped pH profile was found with pK a values of 6.2 and 8.1 either side of this optimum that are associated with protonation/deprotonations that modulate activity. Simulation of the experimental voltammetry elucidated kinetic parameters associated with YiiM catalysis with the substrates 6-hydroxyaminopurine and benzamidoxime., (Copyright © 2021. Published by Elsevier B.V.)

Chemical investigations into solid phase cultivations of an Australian sheep station pasture plant derived Streptomyces sp. CMB-PB042 yielded the rare enamine naphthopyranoquinones BE-54238A ( 1 ) and BE-54238B ( 2 ), together with four new analogues, glenthenamines B-D ( 4 - 6 ) and F ( 8 ), and two handling artifacts, glenthenamines A ( 3 ) and E ( 7 ). Single-crystal X-ray analyses of 1 and 2 resolved configurational ambiguities in the scientific literature, while detailed spectroscopic analysis and biosynthetic considerations assigned structures inclusive of absolute configuration to 3 - 8 . We propose a plausible sequence of biosynthetic transformations linking structural and configurational features of 1 - 8 and apply a novel Schiff base "fishing" approach to detect a key deoxyaminosugar precursor. These enamine naphthopyranoquinones disclose a new P-gp inhibitory pharmacophore capable of reversing doxorubicin resistance in P-gp overexpressing colon carcinoma cells.

Synthesis of the 6-aza[1.0]triblattane skeleton and the unexpected construction of the 7-azatetracyclo[4.2.1.0 2,5 .0 3,7 ]nonane framework are reported, as inspired by the Wilder-Culberson 1-aza[1.1]triblattane ring system. The key steps to assess the 6-aza[1.0]triblattane include accessing the 1,6-cycloaddition product from reaction of chlorosulfonyl isocyanate with cyclohept-1,3,5-triene followed by intramolecular electrocyclization and aminium radical cyclization.

The cytochrome P450 (CYP) superfamily of heme monooxygenases is involved in a range of important chemical biotransformations across nature. Azole-containing molecules have been developed as drugs that bind to the heme center of these enzymes, inhibiting their function. The optical spectrum of CYP enzymes after the addition of these inhibitors is used to assess how the molecules bind. Here we use the bacterial CYP199A4 enzyme, from Rhodopseudomonas palustris HaA2, to compare how imidazolyl and triazolyl inhibitors bind to ferric and ferrous heme. 4-(Imidazol-1-yl)benzoic acid induced a red shift in the Soret wavelength (424 nm) in the ferric enzyme along with an increase and a decrease in the intensities of the δ and α bands, respectively. 4-(1 H -1,2,4-Triazol-1-yl)benzoic acid binds to CYP199A4 with a 10-fold lower affinity and induces a smaller red shift in the Soret band. The crystal structures of CYP199A4 with these two inhibitors confirmed that these differences in the optical spectra were due to coordination of the imidazolyl ligand to the ferric Fe, but the triazolyl inhibitor interacts with, rather than displaces, the ferric aqua ligand. Additional water molecules were present in the active site of 4-(1 H -1,2,4-triazol-1-yl)benzoic acid-bound CYP199A4. The space required to accommodate these additional water molecules in the active site necessitates changes in the position of the hydrophobic phenylalanine 298 residue. Upon reduction of the heme, the imidazole-based inhibitor Fe-N ligation was not retained. A 5-coordinate heme was also the predominant species in 4-(1 H -1,2,4-triazol-1-yl)benzoic acid-bound ferrous CYP199A4, but there was an obvious shoulder at 447 nm indicative of some degree of Fe-N coordination. Rather than inhibit CYP199A4, 4-(imidazol-1-yl)benzoic acid was a substrate and was oxidized to generate a metabolite derived from ring opening of the imidazolyl ring: 4-[[2-(formylamino)acetyl]amino]benzoic acid.

The preparation of a series of alkali-metal inclusion complexes of the molecular cube [{Co III (Me 3 -tacn)} 4 {Fe II (CN) 6 } 4 ] 4- (Me 3 -tacn = 1,4,7-trimethyl-1,4,7-triazacyclononane), a mixed-valent Prussian Blue analogue bearing bridging cyanido ligands, has been achieved by following a redox-triggered self-assembly process. The molecular cubes are extremely robust and soluble in aqueous media ranging from 5 M [H + ] to 2 M [OH - ]. All the complexes have been characterized by the standard mass spectometry, UV-vis, inductively coupled plasma, multinuclear NMR spectroscopy, and electrochemistry. Furthermore, X-ray diffraction analysis of the sodium and lithium salts has also been achieved, and the inclusion of moieties of the form {M-OH 2 } + (M = Li, Na) is confirmed. These inclusion complexes in aqueous solution are rather inert to cation exchange and are characterized by a significant decrease in acidity of the confined water molecule due to hydrogen bonding inside the cubic cage. Exchange of the encapsulated cationic {M-OH 2 } + or M + units by other alkali metals has also been studied from a kineticomechanistic perspective at different concentrations, temperatures, ionic strengths, and pressures. In all cases, the thermal and pressure activation parameters obtained agree with a process that is dominated by differences in hydration of the cations entering and exiting the cage, although the size of the portal enabling the exchange also plays a determinant role, thus not allowing the large Cs + cation to enter. All the exchange substitutions studied follow a thermodynamic sequence that relates with the size and polarizing capability of the different alkali cations; even so, the process can be reversed, allowing the entry of {Li-OH 2 } + units upon adsorption of the cube on an anion exchange resin and subsequent washing with a Li + solution.

Chemical investigation on a Streptomyces sp. strain MS180069 isolated from a sediment sample collected from the South China Sea, yielded the new benzo[f]isoindole-dione alkaloid, bhimamycin J (1). The structure was determined by extensive spectroscopic analysis, including HRMS, 1D, 2D NMR, and X-ray diffraction techniques. A molecular docking study revealed 1 as a new molecular motif that binds with human angiotensin converting enzyme2 (ACE2), recently described as the cell surface receptor responsible for uptake of 2019-CoV-2. Using enzyme assays we confirm that 1 inhibits human ACE2 79.7 % at 25 μg/mL., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

The evidence for the existence of metal complexes containing H 3 O + as a ligand in the solid state is examined. Each of the 68 examples in the Cambridge Structural Database in which H 3 O + is bound to a transition metal, lanthanoid, actinoid, or main group metal ion is detailed and critically appraised. It is concluded that none of the reported examples of complexes containing coordinated H 3 O + have been unequivocally characterized and that they result from either curation errors or misinterpretations of the crystallographic data. These conclusions are supported by computational techniques, which show that three purported H 3 O + complexes based on the 1,4,7,10,13,16,21,24-octa-azabicyclo(8.8.8)hexacosane azacryptand skeleton are better described as aqua complexes, with protonation occurring at the amine ligand.

The rare organocopper(II) complex [Cu(Me 6 tren)(CH 2 CN)] + (Me 6 tren = tris(2-(dimethylamino)ethyl)amine) has emerged as an important model of potential byproducts in copper-catalyzed atom transfer radical polymerization. This complex has been generated by controlled potential electrolysis of [Cu(Me 6 tren)(NCMe)] 2+ in the presence of BrCH 2 CN. Time-resolved UV-vis and continuous wave and pulse electron paramagnetic resonance (EPR) spectra identified [Cu(Me 6 tren)Br] + as an intermediate. Hyperfine sublevel correlation and electron nuclear double resonance spectroscopy of samples at different timepoints reveal signals that are assigned to a C-bound cyanomethylate ligand, with distinct 14 N and 1 H hyperfine coupling constants in comparison with the corresponding N-bound acetonitrile and bromido complexes. The experimental EPR data are supported by density functional theory calculations to understand how the geometries of the species involved produce distinct spectroscopic signatures, and a clear picture of how this unusual organocopper(II) complex is formed has emerged.

The intersection between Cu-catalyzed atom transfer radical polymerization (ATRP) and organometallic mediated radical polymerization (OMRP) has been recently shown to be a result of competition between the Cu I and Cu II complexes of polyamine ligands for the same organic free radical. The tetradentate ligands N , N '-bis-2'-pyridylmethyl-ethane-1,2-diamine (L 1 ) and N , N '-dimethyl- N , N '-bis-2'-pyridylmethyl-ethane-1,2-diamine (L 2 ) form stable Cu complexes which, depending on their oxidation state, can either liberate or complex organic radicals. Herein, we show that this process may be affected by subtle changes to the ligand system. Switching from a tertiary amine (L 2 ) to a secondary amine (L 1 ) retains ATRP and OMRP activity through a series of cyclic voltammetry measurements in the presence of the initiator bromoacetonitrile.

We report on the chemical analysis of a mud dauber wasp nest-associated fungus, Penicillium sp. CMB-MD22, leading to the discovery and structure elucidation of three known ( 1 - 3 ) and two new ( 4 and 5 ) anthrones, and a family of new and known bianthrones, neobulgarones 6 - 23 . Detection and structure elucidation of 1 - 23 was supported by detailed spectroscopic analysis, as well as chemical (thermal) transformations, and global natural products social (GNPS) molecular networking. An empirical approach using HPLC retention times was effective at differentiating anti from syn bianthrone isomers, while a facile thermal equilibration was shown to favor anti over syn isomers. The neobulgarones 6 - 23 are natural products, and a crude extract rich in 6 - 23 exhibits selective antifungal activity against a co-isolated mud dauber wasp nest-associated fungus, suggestive of a possible ecological role as an antifungal chemical defense.

Nitrate reductase (NR) from the fungus Neurospora crassa is a complex homodimeric metallo-flavoenzyme, where each protomer contains three distinct domains; the catalytically active terminal molybdopterin cofactor, a central heme-containing domain, and an FAD domain which binds with the natural electron donor NADPH. Here, we demonstrate the catalytic voltammetry of variants of N. crassa NRs on a modified Au electrode with the electrochemically reduced forms of benzyl viologen (BV 2+ ) and anthraquinone sulfonate (AQS - ) acting as artificial electron donors. The biopolymer chitosan used to entrap NR on the electrode non-covalently and the enzyme film was both stable and highly active. Electrochemistry was conducted on two distinct forms; one lacking the FAD cofactor and the other lacking both the FAD and heme cofactors. While both enzymes showed catalytic nitrate reductase activity, removal of the heme cofactor resulted in a more significant effect on the rate of nitrate reduction. Electrochemical simulation was carried out to enable kinetic characterisation of both the NR:nitrate and NR:mediator reactions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Using a molecular networking guided strategy, chemical analysis of the Australian mullet fish gastrointestinal tract-derived fungus Amauroascus sp. CMB-F713 yielded a family of polyketide pyrones, amaurones A-I ( 1 - 9 ), featuring an unprecedented carbon skeleton. Structures were assigned to 1 - 9 by detailed spectroscopic analysis (including X-ray analysis of 1 ), biosynthetic considerations, and chemical interconversions. For example, the orthoacetate 5 was unstable when stored dry at room temperature, transforming to the monoacetates 2 and 3 , while mild heating (40 °C) prompted quantitative conversion of 3 to 2 , via an intramolecular trans -acetylation. Likewise, during handling, the monoacetate 1 was prone to intramolecular trans -acetylation, leading to an equilibrium mixture with the isomeric monoacetate amaurone J ( 10 ), confirmed when partial hydrolysis of the diacetate 2 yielded the monoacetates 1 and 10 and the triol amaurone K ( 11 ).

The tetradentate N2S2 Schiff base ligands derived from condensing S-methyl or S-benzyl dithiocarbazate with acetylacetone have been found to be versatile chelators for copper and able to stabilise unusually high oxidation states. Herein we report their Ni coordination chemistry and a variety of products ensue depending on the reaction conditions. Unusual examples of linkage isomerism have been observed upon complexation with nickel acetate and these asymmetrically and symmetrically coordinated NiIIN2S2 complexes have been characterised both crystallographically and in solution by NMR. These compounds react rapidly with dioxygen and the ligands are particularly susceptible to oxidation which lead to various products including dinuclear NiII complexes derived from radical homocoupling reactions. These dinuclear NiII complexes are also redox active and spectroelectrochemistry has revealed new electronic transitions from their formally NiIII/NiII mixed valent state.