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Dysphania is an abundant genus of plants, many of which are endemic to the Australian continent, occurring primarily in arid and temperate zones. Despite their prevalence, very few investigations into the phytochemistry of native Dysphania have been undertaken. Described herein, is the isolation and elucidation of two enantiomeric diastereomers of humulene diepoxide C from D. kalpari and D. rhadinostachya, of which unassigned diastereomers of humulene diepoxide C have been previously reported as components in beer brewed from aged hops. In addition, two (+)-humulene diepoxiols (humulene diepoxiol C-I and C-II) were isolated from D. rhadinostachya. Analysis of Chinook hops oil confirmed the presence of both humulene diepoxide C-I and C-II as trace components, and in turn enabled GC-MS peak assignment to the relative stereochemistry. Anticancer assays did not reveal any significant activity for the (+)-humulene diepoxides. Antifungal assays showed good activity against a drug-resistant strain of C. auris, with MIC50 values of 8.53 and 4.91 μm obtained for (+)-humulene diepoxide C-I and C-II, respectively.

The introduction of an amide bond linking side chains of the first and fifth amino acids forms a cyclic pentapeptide that optimally stabilizes the smallest known α-helix in water. The origin of the stabilization is unclear. The observed dependence of α-helicity on the solvent and cyclization linker led us to discover a novel long-range n to π* interaction between a main-chain amide oxygen and a uniquely positioned carbonyl group in the linker of cyclic pentapeptides. CD and NMR spectra, NMR and X-ray structures, modelling, and MD simulations reveal that this first example of a synthetically incorporated long-range n to π* CO⋅⋅⋅Cγ =Ο interaction uniquely enforces an almost perfect and remarkably stable peptide α-helix in water but not in DMSO. This unusual interaction with a covalent amide bond outside the helical backbone suggests new approaches to synthetically stabilize peptide structures in water.

5-(2-Oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) is a natural product formed during bacterial synthesis of vitamin B2. It potently activates mucosal associated invariant T (MAIT) cells and has immunomodulatory, inflammatory, and anticancer properties. This highly polar and unstable compound forms a remarkably stable Schiff base with a lysine residue in major histocompatibility complex class I-related protein (MR1) expressed in antigen-presenting cells. Inspired by the importance of the ribityl moiety of 5-OP-RU for binding to both MR1 and the T cell receptor (TCR) on MAIT cells, each OH was removed in silico. DFT calculations and MD simulations revealed a very stable hydrogen bond between the C3'-OH and uracil N1H, which profoundly restricts flexibility and positioning of each ribityl-OH, potentially impacting their interactions with MR1 and TCR. By using deoxygenation strategies and kinetically controlled imine formation, four monodeoxyribityl and four monohydroxyalkyl analogues of 5-OP-RU were synthesised as new tools for probing T cell activation mechanisms.

Antibacterial-activity-guided fractionation of a dichloromethane extract from the fruit of Cordyline manners-suttoniae and subsequent structure-activity investigations resulted in the identification of 10 new (1-10) and one known (11) 5α-spirostane saponin. The structures of the new compounds were established by 1D and 2D NMR analyses. The absolute configurations of the isolated compounds were determined by X-ray diffraction analysis or chemical derivatizations. The most active compound, suttonigenin F (6), inhibited the Gram-positive bacteria Staphylococcus aureus with MIC75 values that were comparable to those of the antibiotic chloramphenicol. Structure-activity relationships were also obtained from the assessment of antibacterial and cytotoxic activities of the isolated saponins.

The highly oxygenated pimarane diterpenoids basimarols A, B, and C (3–5) were isolated from the plant species Basilicum polystachyon, which was collected within the Australian arid zone. Structure elucidation was performed using a suite of spectroscopic techniques, including X-ray crystallography. Anticancer and anti-DENV activity of 3–5 was explored, but only limited activity was observed. More extensive antiviral evaluation of stachyonic acid A (1), which was also isolated from B. polystachyon, revealed broad spectrum antiviral activity against West Nile virus (Kunjin strain, WNVKun) and human influenza viruses H1N1 and H3N2.

Chemical analysis of Chrysosporium sp. CMB-F214, yielded five new piperazines, chrysosporazines A-E (1-5), with structures assigned by spectroscopic and X-ray analyses and biosynthetic considerations. The chrysosporazines 2-5 exist as an equilibrium of major and minor N-acyl rotamers, while 1-3 incorporate an unprecedented hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one scaffold. The noncytotoxic chrysosporazines reverse doxorubicin drug resistance in P-glycoprotein overexpressing colon carcinoma cells (SW620 Ad300), with 2 delivering a comparable gain in sensitivity to the positive control, verapamil.

18 F-radiolabeled diphenyl gallium thiosemicarbazone was prepared by [18 F] fluoride exchange of a nitrato anion under mild conditions. The diphenyl gallium thiosemicarbazone chloride is easily prepared in gram quantities and can be used at room temperature in the presence of oxygen. The corresponding nitrate complex is prepared using silver nitrate in methanol solvent and can be stored under nitrogen for weeks before radiolabeling. The biodistribution of this new tracer was studied in mice using positron emission tomography (PET).

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 and Cu complexes of polyamine ligands for the same organic free radical. The tetradentate ligands ,'-bis-2'-pyridylmethyl-ethane-1,2-diamine (L) and ,'-dimethyl-,'-bis-2'-pyridylmethyl-ethane-1,2-diamine (L) 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) to a secondary amine (L) retains ATRP and OMRP activity through a series of cyclic voltammetry measurements in the presence of the initiator bromoacetonitrile.

Using a molecular networking guided strategy, chemical analysis of the Australian mullet fish gastrointestinal tract-derived fungus

Three cinnamate derivatives bearing a boronate pinacol ester group para, meta and ortho to the a,b-unsaturated ester group have been synthesized via a solventless, expedited Wittig protocol in the best stereoisomeric ratios yet reported, purified by recrystallization, characterized and analyzed by X-ray crystallography. These are valuable building blocks to biologically active derivatives and are themselves biologically active drug leads, displaying excellent selectivities as glycosidase modulators and for future testing as boron neutron capture therapy (BNCT) agents. In a panel of 15 glycosidases, IC50 values of 351 mM and 374 mM were shown for para 2 against almond b-glucosidase and bovine liver b-galactosidase, respectively. For meta 2 the selectivity profile is improved with only inhibition of bovine liver b-galactosidase with an IC50 of 780 mM. These borylated derivatives also possess the capability to be used as BNCT agents. This occurs via irradiation with slow neutrons, thus granting them a switch-on/switch-off toxicity. This is an important new capability imbued into anticancer drugs, too many of which are too toxic in their therapeutic window. BNCT drugs bearing the organic boron pharmacophore have the potential to fine-tune the timing of toxicity delivery.

The preparation of a series of alkali-metal inclusion complexes of the molecular cube [{CoIII(Me3-tacn)}4{FeII(CN)6}4]4- (Me3-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-OH2}+ (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-OH2}+ 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-OH2}+ units upon adsorption of the cube on an anion exchange resin and subsequent washing with a Li+ solution., Financial support by Grant PID2019-107006GB-C21 funded by MCIN/AEI/10.13039/501100011033 is acknowledged.

During the last 150 years or more, society has witnessed many key scientific discoveries and inventions, which have dramatically improved not only our quality of life, but our lifespan. However, the motivation of scientists to provide scientific advances has generally not been the achievement of these goals, but mainly driven by research curiosity. Fundamental scientific studies, also known as basic science, have paved the way to a society of knowledge by means of continuously evolving education systems, and have led to applied science and technological breakthroughs changing the World. However, without basic science such life-changing advances would not happen, which is poorly understood by the society. Having this in mind, chemists and biochemists working in a chemistry network highlight here examples of how basic science has played a crucial role and led to major breakthroughs. In seven short stories, the authors describe cases and historical events where basic research discoveries have advanced science, and opened avenues for future achievements. Investment in basic science is crucial for a nation’s health and wealth. The support of scientists driven by curiosity ultimately can benefit the whole of society, not only in innovative products, but also in the improvement of the understanding of our own lives.

Short syntheses to high Fsp 3 index natural-product analogues such as imino­sugars are of paramount importance in the investigation of their biological activities and reducing the use of protecting groups is an advantageous synthetic strategy. In this case only an iso­propyl­idene group was employed towards the synthesis of seven-membered ring imino­sugars., Short syntheses to high Fsp 3 index natural-product analogues such as imino­sugars are of paramount importance in the investigation of their biological activities and reducing the use of protecting groups is an advantageous synthetic strategy. An iso­propyl­idene group was employed towards the synthesis of seven-membered ring imino­sugars and the title compound, C9H15N3O5, was crystallized as an inter­mediate, in which the THF ring is twisted and the dioxolane ring adopts an envelope conformation: the dihedral angle between the rings is 67.50 (13)°. In the crystal, the hydroxyl groups participate in O—H⋯(O,O) and O—H⋯N hydrogen-bonding inter­actions, which generate chains of mol­ecules propagating parallel to the a-axis direction. There is a notable non-classical C—H⋯O hydrogen bond, which cross-links the [100] chains into (001) sheets.

The copper coordination chemistry of N2S2 Schiff base ligands derived from acetylacetone and S-methyl or S-benzyl dithiocarbazate (H3acacsR, R = Me, Bn) reveals a rich variety of products depending on the reaction conditions. The free ligands spontaneously cyclise to their pyrazoline isomers but ring-open upon complexation with CuII. In the absence of oxygen, the ligands form CuIIN2S2 complexes ([CuII(HacacsR)]) that have been characterised electrochemically, spectroscopically and structurally. Intermediates in the complexation reaction are observed with time-resolved UV-Vis spectroscopy. Upon exposure to air, a number of different complexes are formed. Facile oxidation of [CuII(HacacsR)] to the trivalent analogue [CuIII(acacsR)] occurs in air. This compound is the precursor to two further oxidation reactions; one to the ketone [CuII(acacsRO)] where a carbonyl group has been installed at the apical C atom of the acetylacetone moiety and another to afford the novel dinuclear complex [(CuIII(acacsR))2]. The presence of excess base (Et3N) favours formation of the dimer.

Bismuth-based organohalides have attracted much attention as potential alternatives to lead halide perovskites and have been explored in various electronic and optoelectronic devices. Developing new bismuth organohalides with rational design has been a dynamic research area. Herein, we developed single-crystals and thin-films of a new class of bismuth-based organohalides (phenethylammonium (C8H12N+, PEA+) bismuth halides). We found that comparable optical properties can be preserved after replacing methylammonium with bulky PEA+ cations. The bulky PEA+ cation significantly promotes the coverage and low surface roughness of bismuth organohalide thin-films in a facile one-step solution method. Newly-prepared (PEA)3Bi2I9 also shows excellent thermal and humidity stability, showing promise for addressing the toxicity and stability of optoelectronic/electronic devices beyond lead halide perovskites.

The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.

Recent experimental observations of the role played by copper polyamine catalysts in atom transfer radical polymerisation (ATRP) have indicated that important side reactions in competition with conventional radical activation by halogen atom transfer may occur and that these can potentially affect reaction control. Specifically the copper(I) catalyst may recapture the organic radical and even possibly abstract H-atoms from the radical to form copper(II) alkyl or hydrido complexes. Employing an established electrochemical methodology and supported by Density Functional Theory calculations, we report a systematic experimental and theoretical investigation of the ATRP catalyst [Cu(Me6tren)]+ (Me6tren = tris(2-dimethylaminoethyl)amine) and its reactions with a homologous series of bromo-ester initiators that yield tertiary, secondary and primary radicals. The results reveal that organocopper(II) complexes are preferred to hydrido complexes and that increasing steric bulk at the initiator steers the reaction pathway away from the organocopper complex and toward the desired ATRP product.

A GNPS molecular networking approach mapped a library of 960 southern Australian marine sponges and prioritized

The cytochrome P450 superfamily of heme monooxygenases catalyzes important chemical reactions across nature. The changes in the optical spectra of these enzymes, induced by the addition of substrates or inhibitors, are critical for assessing how these molecules bind to the P450, enhancing or inhibiting the catalytic cycle. Here we use the bacterial CYP199A4 enzyme (Uniprot entry Q2IUO2), from Rhodopseudomonas palustris HaA2, and a range of substituted benzoic acids to investigate different binding modes. 4-Methoxybenzoic acid elicits an archetypal type I spectral response due to a ≥95% switch from the low- to high-spin state with concomitant dissociation of the sixth aqua ligand. 4-(Pyridin-3-yl)- and 4-(pyridin-2-yl)benzoic acid induced different type II ultraviolet-visible (UV-vis) spectral responses in CYP199A4. The former induced a greater red shift in the Soret wavelength (424 nm vs 422 nm) along with a larger overall absorbance change and other differences in the α-, β-, and δ-bands. There were also variations in the ferrous UV-vis spectra of these two substrate-bound forms with a spectrum indicative of Fe-N bond formation with 4-(pyridin-3-yl)benzoic acid. The crystal structures of CYP199A4, with the pyridinyl compounds bound, revealed that while the nitrogen of 4-(pyridin-3-yl)benzoic acid is coordinated to the heme, with 4-(pyridin-2-yl)benzoic acid an aqua ligand remains. Continuous wave and pulse electron paramagnetic resonance data in frozen solution revealed that the substrates are bound in the active site in a form consistent with the crystal structures. The redox potential of each CYP199A4-substrate combination was measured, allowing correlation among binding modes, spectroscopic properties, and the observed biochemical activity.

The complexation reaction mechanism of acetylacetone bis-thiosemicarbazone ligands (HacacR) with Cu is explored using a variety of physical methods. The complexes form via a complicated multistep mechanism that is initiated by ring opening of the pyrazoline form of the ligand and leads, ultimately in air, to an oxidised ketone form of the ligand. Tetradentate NS coordinated forms of the intermediate [Cu(acacR)] are stable only under anaerobic conditions. Upon exposure to air these complexes are cleanly oxidised to the ketone complex [Cu(acacRO)] as shown by X-ray crystallography, electrochemistry, UV/Vis and EPR spectroscopy. The behavior of these complexes contrasts with those of closely related bis-dithiocarbazate Schiff bases which stabilise Cu.

Gallium complexes of bis-thiosemicarbazones were prepared and characterized using NMR and X-ray crystallography. Formation of a gallium nitrate complex was proven by NMR spectroscopy. Surprisingly, this complex was found to convert on standing to a new hydroxido-bridged di-gallium complex. The X-ray crystal structure of the digallium complex is described. Similarly, a triazene compound was formed during the preparation of the gallium complex comprising a tetraphenyl unit in the bis-thiosemicarbazone structure. We propose a mechanism for the formation of both the di-gallium species as well as triazene compound in solution. The lattice parameters for the digallium complex is as follows: a: 17.6854(13) A, b:16.6492(7) A, c: 21.4659(14) A, β = 112.383(8)°.

The coordination chemistry of copper is dominated by its monovalent and divalent oxidation states and interplay between the two is central to the role of copper-based homogeneous catalysts. Upon reduction of most copper(II) complexes, which commonly are five coordinate, the coordination number rapidly changes to four or less. This feature is advantageous for atom transfer reactions where single electron transfer is coupled to the association or dissociation of a radical. Although this coupled change in coordination number and oxidation state is central to the mechanism of atom transfer reactions, its importance to catalysis is not widely appreciated. Herein we review the structural chemistry of copper(I) and copper(II) with a range of multidentate N-donor ligands employed in atom transfer radical polymerisation (ATRP). The remarkable resistance of copper(I) to accept more than four donor atoms is illustrated and discussed in the context of both its solid state and solution structures.

The Ley–Griffith oxidation, which is catalyzed by tetra-n-propylammonium perruthenate (TPAP, nPrN[RuO]), is a popular method for not only controlled oxidation of primary alcohols to aldehydes, but also a host of other synthetically useful transformations. While the fundamental reaction mechanism has recently been elucidated, several key hydrogen-bonding interactions between the reagents were implicated but not investigated. Herein the prevalence of H-bonding between the co-oxidant N-methylmorpholine N-oxide (NMO), the alcohol substrate, water and the perruthenate catalyst is established. These observations help to rationalize the importance of drying the reagents and lead to several practical suggestions.

The crystal structure of ethyl 2,4-dimethyl-1-phenyl-6-thioxo-1,6-dihydropyrimidine-5-carboxylate (7) has been determined (monoclinic, P21/n, a 12.5543(9); b 7.6345(4); c 16.1568(14) A, β 107.210(9)°) revealing a thioamide functional group instead of the thiazine ethyl (Z)-2,4-dimethyl-6-(phenylimino)-6H-1,3-thiazine-5-carboxylate (5) proposed previously. This has required the revision of the published structure for this multicomponent reaction which now has identified (7), not (5), as the product, supported by NMR and IR analysis. The crystal structure of the major product from the reaction of ethyl 3-aminocrotonate, phenylisothiocyanate and acetic anhydride is ethyl 2,4-dimethyl-1-phenyl-6-thioxo-1,6-dihydropyrimidine-5-carboxylate (shown), not the previously identified ethyl (Z)-2,4-dimethyl-6-(phenylimino)-6H-1,3-thiazine-5-carboxylate.

We report electrochemically driven catalysis of the complex molybdoenzyme steroid C25 dehydrogenase (S25DH) from the β-Proteobacterium Sterolibacterium denitrificans. S25DH catalyzes the oxygen-independent regioselective hydroxylation of the tertiary C25 atom of sterols and also their derivatives. Cholest-4-en-3-one is a native substrate for S25DH, which produces 25-hydroxy-cholest-4-en-3-one as a product of catalytic turnover. Cholecalciferol (vitD3) is also a substrate. S25DH was immobilized on a modified Au working electrode with the co-adsorbent chitosan. The complexes ferricyanide ([Fe(CN)6]3-) and ferrocenium methanol (FM+) are effective artificial electron acceptors from S25DH and act as mediators of electron transfer between the electrode and the enzyme. 2-Hydroxypropyl-β-cyclodextrin (HPCD) was employed as a sterol solubilizer in addition to 2-methoxyethanol. The catalytic activity varied depending upon the concentration of solubilizer in the reaction mixture. Parallel studies using ferricyanide as a chemical (as opposed to electrochemical) oxidant coupled to HPLC analysis show that S25DH is capable of oxidising both vitD3 and its less stable isomer pre-vitD3 and that the former substrate is stabilised by HPCD.

Cyclic peptides, especially those produced by marine cyanobacteria symbionts, are considered to play an important ecological role in host defence. Chemists have long compared the cyclic peptide cavitand architecture with that of macrocyclic ligands, and proposed that they mediate metal-ion transport. The study presented herein investigated the metal chelation of non-natural heteroatom-interchanged (HI) isomers of lissoclinamide 5, by using MS, EPR, and DFT calculations. The latter identified three possible structures for the Cu complex with natural lissoclinamide 5, with the most likely determined to be that with the metal ion bound through the nitrogen donors of the thiazoles and one deprotonated amide. For HI-lissoclinamide 5 the calculations suggest that the Cu ion is bound in a bidentate manner by the oxazoline nitrogen atom and one deprotonated amide nitrogen atom, with the S donor of the thiazole not involved in coordination. Along with evidence of copper binding these systems also bound halide ions. Evaluation of the anti-cancer properties demonstrated that the biological activity of HI-lissoclinamide 5 against T24 bladder cells was eleven-fold lower as compared to natural lissoclinamide 5. Addition of a Cu salt had no effect on the activity of lissoclinamide 5. Overall, this comprehensive study of the HI concept has demonstrated that small changes propagate dramatic effects in complexation, halide binding, and biological activity.

A central conserved arginine, first identified as a clinical mutation leading to sulfite oxidase deficiency, is essential for catalytic competency of sulfite oxidizing molybdoenzymes, but the molecular basis for its effects on turnover and substrate affinity have not been fully elucidated. We have used a bacterial sulfite dehydrogenase, SorT, which lacks an internal heme group, but transfers electrons to an external, electron accepting cytochrome, SorU, to investigate the molecular functions of this arginine residue (Arg78). Assay of the SorT Mo centre catalytic competency in the absence of SorU showed that substitutions in the central arginine (R78Q, R78K and R78M mutations) only moderately altered SorT catalytic properties, except for R78M which caused significant reduction in SorT activity. The substitutions also altered the Mo-centre redox potentials (MoVI/V potential lowered by ca. 60-80mV). However, all Arg78 mutations significantly impaired the ability of SorT to transfer electrons to SorU, where activities were reduced 17 to 46-fold compared to SorTWT, precluding determination of kinetic parameters. This was accompanied by the observation of conformational changes in both the introduced Gln and Lys residues in the crystal structure of the enzymes. Taking into account data collected by others on related SOE mutations we propose that the formation and maintenance of an electron transfer complex between the Mo centre and electron accepting heme groups is the main function of the central arginine, and that the reduced turnover and increases in KMsulfite are caused by the inefficient operation of the oxidative half reaction of the catalytic cycle in enzymes carrying these mutations.

Alzheimer's disease (AD) is characterized by multiple pathological hallmarks, including β-amyloid aggregation, oxidative stress, and metal dys-homeostasis. In the absence of treatments addressing its multi-factorial pathology, we designed novel multi-functional adamantane-based semicarbazones and hydrazones (1-12) targeting AD hallmarks. Of these, 2-pyridinecarboxaldehyde (N-adamantan-1-yl)benzoyl-4-amidohydrazone (10) was identified as the lead compound, which demonstrated: (1) pronounced iron chelation efficacy; (2) attenuation of CuII-mediated β-amyloid aggregation; (3) low cytotoxicity; (4) inhibition of oxidative stress; and (5) favorable characteristics for effective blood-brain barrier permeation. Structure-activity relationships revealed that pyridine-derived hydrazones represent a promising pharmacophore for future design strategies due to their ability to bind critical FeII pools. Collectively, the unique multi-functional activity of these agents provides a novel therapeutic strategy for AD treatment.

We report an electrochemical nitrate biosensor incorporating the enzyme nitrate reductase (NR) from the fungus Neurospora crassa entrapped within a polymeric chitosan matrix on a glassy carbon (GC) electrode. The artificial electron mediator anthraquinone sulfonate (AQ) is utilized as an electron transfer partner (co-substrate) for NR. The NR enzyme was effectively immobilized within the chitosan matrix without the need for a dialysis membrane, and exhibited high sensitivity and selectivity for nitrate using either rotating disk cyclic voltammetry or constant potential amperometry methods. A particular feature was the longevity of the biosensor which retained more than 70% activity over a period of 3 months. The practical application of the biosensor was demonstrated by the determination of nitrate concentrations in lake and river water samples without any pre-treatment, and the results were validated with a reliable spectroscopic assay.

As recently as 2006 the mitochondrial amidoxime reducing component (mARC) was identified as the fourth and last Mo enzyme present in humans. Its physiological role remains unknown. mARC is capable of reducing a variety of N-hydroxylated compounds such as amidoximes to their corresponding amidine and there is considerable interest in this enzyme from a pharmaceutical perspective. mARC is a target for N-hydroxylated pro-drugs that may be reductively activated intracellularly to release potent drugs such as cationic amidinium ions, which exhibit a broad spectrum of activity as antithrombotics and against various bacteria and parasites. In the quest for a rapid screen of new mARC substrates and inhibitors we present an electrochemical method which utilizes the natural electron partner of mARC, cytochrome b5, coupled to an electrochemical electrode. Mediated electron transfer from the electrode via cytochrome b5 to mARC results in a catalytic current in the presence of substrate. Keywords: mARC, Molybdenum, Enzyme, Voltammetry, Cytochrome

Air oxidation of methanolic solutions of biologically active tridentate pyridyl thiosemicarbazone (TSC) complexes of the general formula [FeII(TSC)2] has been studied at varying dioxygen concentrations, temperatures, and pressures. The data collected indicate that the activation entropy of the reaction increases linearly with the redox potential of the complexes in a more definite way than the activation enthalpy. However, a very distinct behavior is observed for the values of the activation volumes, which do not follow the expected entropy-volume parallel trend for all of the systems studied. The involvement of important interactions between the terminal NH groups of the coordinated TSC ligand and molecular dioxygen has been found to be significant by measurements carried out at varying hydrostatic pressures. Kinetic experiments run on analogous N-deuterated complexes confirm the importance of these noncovalent interactions, which are weaker for the less acidic ND groups. These interactions show the existence of an ordering/expansion process upon going from the reactants to the transition state, whenever an interaction between the polar terminal amino groups and dioxygen can be established.

Over 44 million people live with Alzheimer's disease (AD) worldwide. Currently, only symptomatic treatments are available for AD and no cure exists. Considering the lack of effective treatments for AD due to its multi-factorial pathology, development of novel multi-target-directed drugs are desirable. Herein, we report the development of a novel series of thiosemicarbazones derived from 1-benzylpiperidine, a pharmacophore within the acetylcholinesterase inhibitor, Donepezil. These thiosemicarbazones were designed to target five major AD hallmarks, including: low acetylcholine levels, dysfunctional autophagy, metal dys-homeostasis, protein aggregation and oxidative stress. Of these thiosemicarbazones, pyridoxal 4-N-(1-benzylpiperidin-4-yl)thiosemicarbazone (PBPT) emerged as the lead compound. This agent demonstrated the most promising multi-functional activity by exhibiting very low anti-proliferative activity, substantial iron chelation efficacy, inhibition of copper-mediated amyloid-β aggregation, inhibition of oxidative stress, moderate acetylcholinesterase inhibitory activity and autophagic induction. These diverse properties highlight the potential of the lead ligand, PBPT, as a promising multi-functional agent for AD treatment.

Direct electrochemistry of human sulfite oxidase (HSO) has been achieved on carboxylate-terminated self-assembled monolayers cast on a Au working electrode in the presence of the promoter chitosan. The modified electrode facilitates a well-defined nonturnover redox response from the heme cofactor (FeIII/II) in 750 mM Tris, MOPS, and bicine buffer solutions. The formal redox potential of the nonturnover response varies slightly depending on the nature of the thiol monolayer on the Au electrode. Upon addition of sulfite to the cell a pronounced catalytic current from HSO-facilitated sulfite oxidation is observed. The measured catalytic rate constant (kcat) is around 0.2 s–1 (compared with 26 s–1 obtained from solution assays), which indicates that interaction of the enzyme with the electrode lowers overall catalysis although native behavior is retained in terms of substrate concentration dependence, pH dependence, and inhibition effects. In contrast, no catalytic activity is observed when HSO is confined to...

We demonstrate electrochemically driven catalytic voltammetry of the Mo-dependent sulfite dehydrogenase (SorT) from the -Proteobacterium Sinorhizobium meliloti with its physiological electron acceptor, the c-type cytochrome (SorU) with both proteins co-adsorbed on a chemically modified Au working electrode. Both SorT and SorU were constrained under a perm-selective dialysis membrane with the biopolymer chitosan as a co-adsorbate while the electrode was modified by a 3-mercaptopropionate self-assembled monolayer cast on the Au electrode. Cyclic voltammetry of the SorU protein reveals a well-defined quasi-reversible FeIII/II redox couple at +130 mV vs NHE in 100 mM phosphate buffer solution (pH 7.0). Introduction of wild type sulfite dehydrogenase (SorTWT) and sulfite transforms this transient SorU voltammetric response into a sigmoidal catalytic wave which increases with sulfite concentration before eventually saturating. In addition to the wild type enzyme, the variants SorTR78K, SorTR78M and SorTR78Q were also examined electrochemically in an effort to better understand the role of amino acid residue Arg78 which is in the vicinity of the Mo active site of SorT.

International audience; The first stereocontrolled Cu-catalyzed sequential 1,6/1,4-asymmetric conjugate addition (ACA) of C-metalated hard nucleophiles to cyclic dienones is reported. The use of DiPPAM (diphenylphosphinoazomethinylate) followed by a phosphoramidite as the stereoinducing ligands facilitated both high ee values for the 1,6-ACA and high de values for the 1,4-ACA reaction components, which thus gave enantioenriched 1,3-dialkylated moieties. The absolute configurations were determined by using vibrational circular dichroism (VCD) and optical rotatory dispersion (ORD) spectroscopy, in combination with DFT calculations and X-ray analysis. Interestingly, DFT calculations for the mechanism of enantioselective 1,6-addition by using an unprecedented Cu-Zn bimetallic catalytic system confirmed this attribution. Lastly, exploring intramolecular cyclization avenues for enantioenriched 1,3-dialkylated products provided access to the challenging drimane skeleton.

NMR and single crystal X-ray structure data for four structurally similar semicarbazones and thiosemicarbazones were compared. In solution, proton NMR showed considerable variation in their chemical shift values especially for the NH2 protons. In the case of the semicarbazones this peak appeared as a broad singlet with an integration ratio of two while for the thiosemicarbazones the amino group showed two distinct singlets with marked chemical shift differences. This is attributed to the differences in the canonical forms of the thiosemicarbazone amino group and the semicarbazone analogue. Additionally, we provide evidence that the 2-trifluoromethyl phenyl substituted semicarbazone (2) formed an intermolecular hydrogen bond with one of the hydrogens of the NH2 group while this was totally absent in the thiosemicarbazone. We explain this by the restricted rotation of the CN bond in the thiosemicarbazone due to its double bond character compared to the less restricted rotation in semicarbazone compound. NMR and single crystal X-ray structure data for four structurally similar semicarbazones and thiosemicarbazones were compared for their hydrogen bonding characteristics.

The widely occurring tetranortriterpene natural product gedunin has a well-established range of important biological properties. Although this molecule has received substantial semi-synthetic attention from medicinal chemists, it has not received devoted de novo synthetic attention since it was first isolated in 1960. A key feature of the approach presented herein was the decision to utilize a Robinson annulation reaction, which facilitated the installation of the challenging 7-acetoxy functional group and the completion of the fully functionalized ABC ring system.

Gedunin, first isolated in 1960, displays a remarkable range of biological activity, but has yet to receive dedicated synthetic attention from a ground up construction perspective. Presented herein is a successfully executed approach to the fully functionalized ABC ring system of this challengingly complex natural product.

Chemical analysis of the fungus

The kinetics of oxidation of different biologically-active FeII bis-thiosemicarbazone complexes in water has been monitored at varying dioxygen concentration, temperature, pressure, and pH. The oxidation reactions observed can be resolved as a single-step process, producing the expected ferric complex, with rates increasing with decreasing pH. From the pH-dependence of the observed rate constants, a rate law with two terms can be derived, one of them being independent of the acid concentration and the other term showing a saturation behaviour with respect to [H+]. These results indicate the existence of two parallel pathways for oxidation: the acid-independent pathway is only operative for the complexes with ligands bearing terminal, non-coordinated, unsubstituted amines, whereas the term with a [H+]-limiting kinetic behaviour is observed for all the complexes and indicates that the reacting species has to be protonated prior to the oxidation step. From the data collected, the rate law and the thermal and pressure activation parameters have been used to interpret the operating reaction mechanisms. Given the fact that the empirical trends rule out an outer-sphere oxidation process, DFT calculations have been carried out to explain the results and suggest the likely formation, under steady-state very low concentration conditions, of FeIII superoxo and hydroperoxo intermediates.

Phorbol esters are long regarded as tumor promotors, due to protein kinase C (PKC) activation, but more recently higher oxidized natural derivatives have been shown to display antitumor activity. Given the synthetic difficulty, systematic non-natural systems are not readily available to further interrogate PKC binding. Herein reported is the concise construction of a considerably advanced intermediate toward D-ring inverted phorbol esters, enabled by a rhodium-catalyzed [4 + 3] cycloaddition involving a highly functionalized tetrahydrobenzofuran.

The highly oxygenated pimarane diterpenoids basimarols A, B, and C (

Chemical analysis of

CO dehydrogenase (CODH) from the Gram-negative bacterium Oligotropha carboxidovorans is a complex metalloenzyme from the xanthine oxidase family of molybdenum-containing enzymes, bearing a unique binuclear Mo-S-Cu active site in addition to two [2Fe-2S] clusters (FeSI and FeSII) and one equivalent of FAD. CODH catalyzes the oxidation of CO to CO2 with the concomitant introduction of reducing equivalents into the quinone pool, thus enabling the organism to utilize CO as sole source of both carbon and energy. Using a variety of EPR monitored redox titrations and spectroelectrochemistry, we report the redox potentials of CO dehydrogenase at pH 7.2 namely MoVI/V, MoV/IV, FeSI2+/+, FeSII2+/+, FAD/FADH and FADH/FADH−. These potentials are systematically higher than the corresponding potentials seen for other members of the xanthine oxidase family of Mo enzymes, and are in line with CODH utilising the higher potential quinone pool as an electron acceptor instead of pyridine nucleotides. CODH is also active when immobilised on a modified Au working electrode as demonstrated by cyclic voltammetry in the presence of CO.

Tuberculosis is one of the oldest known infectious diseases, responsible for millions of deaths annually around the world. The ability of Mycobacterium tuberculosis (Mtb) to enter into a dormant state has been considered integral to the success of this bacterium as a human pathogen. One of the key systems involved in regulating the entrance into dormancy is the differentially expressed in virulent strain sensor protein (DevS) [(dormancy survival sensor protein (DosS)]. However, the physiological signal for DevS has remained unclear since it was first shown to be a heme-based sensor with conflicting reports on whether it is a redox or an oxygen sensor. To address this question and provide a better understanding of the electronic properties of this protein, we present here, for the first time, a series of spectroelectrochemistry measurements of the full-length holo DevS in anaerobic conditions as well as bound to CO, NO, imidazole (Imz), cyanide, and O-2. An interesting feature of this protein is its ability to bind Imz even in the ferrous state, implying small-molecule analogues could be designed as potential regulators. Nonetheless, a midpoint potential (E-m) value of +10 mV [vs normal hydrogen electrode (NHE)] for DevS as measured under anaerobic conditions is much higher than the expected cytosolic potential for Mtb or even within stimulated macrophages (similar to -270 mV vs NHE), indicating this sensor works in a reduced ferrous state. These data, along with the high oxygen affinity and very slow auto-oxidation rate of DevS, provides evidence that it is not a redox sensor. Overall, this study validates the biological function of DevS as an oxygen sensor directly involved in the dormancy/latency of Mtb.