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Synthesis of the 6-aza[1.0]triblattane skeleton and the unexpected construction of the 7-azatetracyclo[4.2.1.0

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 Mg2+ and Mn2+) were investigated. Rate measurements demonstrate that the presence of stoichiometric concentrations Mn2+ promotes higher activity than Mg2+, 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 Mn2+ (not Mg2+) to this site affects the ligand environment of the catalytically essential divalent metal binding site, thus providing insight into an inhibitory mechanism of Mn2+ 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.

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.

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).

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

Dysphania is a genus of plants endemic to the Australian continent, occurring primarily in arid and temperate zones. Despite their prevalence, very little in the way of phytochemical and/or bioacti...

A GNPS molecular networking approach mapped a library of 960 southern Australian marine sponges and prioritized Dysidea sp. (CMB-01171) for chemical investigation. Although the published natural pr...

Chemical analysis of the fungus Chrysosporium sp. CMB-F294 isolated from the gastrointestinal tract of a market-purchased specimen of Mugil mullet yielded eight new alkaloids, belonging to a rare class of phenylpropanoid piperazines. Chrysosporazines F–M (1–8) occur as an equilibrium mixture of acetamide rotamers and feature unprecedented carbocyclic and heterocyclic scaffolds. Structures inclusive of absolute configuration were assigned by detailed spectroscopic analysis, supported by biosynthetic considerations. Structure–activity relationship studies determined that selected chrysosporazines were promising noncytotoxic inhibitors of the multidrug resistance efflux pump P-glycoprotein (P-gp), capable of reversing doxorubicin resistance in P-gp-overexpressing human colon carcinoma cells (SW620 Ad300). Chrysosporazine F (1) was particularly noteworthy, with a 2.5 μM cotreatment inducing a doxorubicin gain in sensitivity (GS 14) > 2-fold that of the positive control verapamil (GS 6.1).

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.

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 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.

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.

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.

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.

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.

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.

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 Ley–Griffith reaction is utilized extensively in the selective oxidation of alcohols to aldehydes or ketones. The central catalyst is commercially available tetra-n-propylammonium perruthenate (TPAP, n-Pr4N[RuO4]) which is used in combination with the co-oxidant N-methylmorpholine N-oxide (NMO). Although this reaction has been employed for more than 30 years, the mechanism remains unknown. Herein we report a comprehensive study of the oxidation of diphenylmethanol using the Ley–Griffith reagents to show that the rate determining step involves a single alcohol molecule, which is oxidised by a single perruthenate anion; NMO does not appear in rate law. A key finding of this study is that when pure n-Pr4N[RuO4] is employed in anhydrous solvent, alcohol oxidation initially proceeds very slowly. After this induction period, water produced by alcohol oxidation leads to partial formation of insoluble RuO2, which dramatically accelerates catalysis via a heterogeneous process. This is particularly relevant in a synthetic context where catalyst degradation is usually problematic. In this case a small amount of n-Pr4N[RuO4] must decompose to RuO2 to facilitate catalysis.

MCC950 is an orally bioavailable small molecule inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that exhibits remarkable activity in multiple models of inflammatory disease. Incubation of MCC950 with human liver microsomes, and subsequent analysis by HPLC–MS/MS, revealed a major metabolite, where hydroxylation of MCC950 had occurred on the 1,2,3,5,6,7-hexahydro-s-indacene moiety. Three possible regioisomers were synthesized, and coelution using HPLC–MS/MS confirmed the structure of the metabolite. Further synthesis of individual enantiomers and coelution studies using a chiral column in HPLC–MS/MS showed the metabolite was R-(+)- N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (2a). Incubation of MCC950 with a panel of cytochrome P450 enzymes showed P450s 2A6, 2C9, 2C18, 2C19, 2J2, and 3A4 catalyze the formation of the major metabolite 2a, with a lower level of activity shown by P450s 1A2 and 2B6. All of th...

We report the first electrochemical study of a lanthanoid-dependent methanol dehydrogenase (Eu-MDH) from the acidophilic verrucomicrobial methanotroph Methylacidiphilum fumariolicum SolV with its own physiological cytochrome cGJ electron acceptor. Eu-MDH harbours a redox active 2,7,9-tricarboxypyrroloquinoline quinone (PQQ) cofactor which is non-covalently bound but coordinates trivalent lanthanoid elements including Eu3+ . Eu-MDH and the cytochrome were co-adsorbed with the biopolymer chitosan and cast onto a mercaptoundecanol (MU) monolayer modified Au working electrode. Cyclic voltammetry of cytochrome cGJ reveals a well-defined quasi-reversible FeIII/II redox couple at +255 mV vs. NHE at pH 7.5 and this response is pH independent. The reversible one-electron response of the cytochrome cGJ transforms into a sigmoidal catalytic wave in the presence of Eu-MDH and its substrates (methanol or formaldehyde). The catalytic current was pH-dependent and pH 7.3 was found to be optimal. Kinetic parameters (pH dependence, activation energy) obtained by electrochemistry show the same trends as those obtained from an artificial phenazine ethosulfate/dichlorophenol indophenol assay.

Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either out performed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.

The direct and quantitative reduction of the air-stable Cu(II)Br2/Me6TREN to Cu(0) by NaBH4 represents a new method for the aqueous single electron transfer-living radical polymerization (SET-LRP) of water soluble polymers. By changing the stoichiometry of NaBH4 to Cu(II)Br2, any desired ratio of Cu(II)Br2 to Cu(0) could be obtained with no evidence of Cu(I) species. This quantitative reduction to Cu(0) in combination with rapid disproportionation of Cu(I)Br/Me6TREN in water resulted in activation by Cu(0) initially and during the polymerization. Polymerizations of NIPAM produced polymer within minutes and with controlled and narrow molecular weight distributions in agreement with ideal ‘living’ radical behavior. The direct in situ thio-bromo ‘click’ reaction produce polymers with stable chain-end functionality, eliminating the concern of hydrolysis of the halide end-group (i.e. Br). It was found that the end-group functionality was greater than 95%, and for the very rapid polymerizations close to 100%.

Viridicatumtoxins, which belong to a rare class of fungal tetracycline-like mycotoxins, were subjected to comprehensive spectroscopic and chemical analysis, leading to reassignment/assignment of absolute configurations and characterization of a remarkably acid-stable antibiotic scaffold. Structure activity relationship studies revealed exceptional growth inhibitory activity against vancomycin-resistant Enterococci (IC50 40 nM), >270-fold more potent than the commercial antibiotic oxytetracycline.

An efficient method to directly access the bicyclo[5.3.0]decane core was achieved by rhodium-catalyzed reaction of a novel donor-acceptor cyclopentenyl diazocarboxylate with a variety of furans. As this motif is commonly found within bioactive antitumor natural products, selected systems were further manipulated and evaluated against cancer cell lines sensitive to protein kinase C (PKC) activation. A cyclic donor-acceptor diazo compound was synthesized for the first time, facilitating direct access to the bicyclo[5.3.0]decane motif, which is commonly seen in a number of prominent natural products active against cancer. Some examples were evaluated against various PKC cancer cell lines.

The Ley-Griffith tetra-n-propylammonium perruthenate (TPAP) catalyst has been widely deployed by the synthesis community, mainly for the oxidation of alcohols to aldehydes and ketones, but also for a variety of other synthetic transformations (e.g. diol cleavage, isomerizations, imine formation and heterocyclic synthesis). Such popularity has been forged on broad reaction scope, functional group tolerance, mild conditions, and commercial catalyst supply. However, the mild instability of TPAP creates preparation, storage, and reaction reproducibility issues, due to unpreventable slow decomposition. In search of attributes conducive to catalyst longevity an extensive range of novel perruthenate salts were prepared. Subsequent evaluation unearthed a set of readily synthesized, bench stable, phosphonium perruthenates (ATP3 and MTP3) that mirror the reactivity of TPAP, but avoid storage decomposition issues.

International audience; Single crystal structural analysis of [Fe-II(tame)(2)]Cl-2 center dot MeOH (tame = 1,1,1-tris(aminomethyl)-ethane) as a function of temperature reveals a smooth crossover between a high temperature high-spin octahedral d(6) state and a low temperature low-spin ground state without change of the symmetry of the crystal structure. The temperature at which the high and low spin states are present in equal proportions is T-1/2 = 140K. Single crystal, variable-temperature optical spectroscopy of [Fe-II(tame)(2)]Cl-2 center dot MeOH is consistent with this change in electronic ground state. These experimental results confirm the spin activity predicted for [Fe-II(tame)(2)](2+) during its de novo artificial evolution design as a spin-crossover complex [Chem. Inf. Model. 2015, 55, 1844], offering the first experimental validation of a functional transition-metal complex predicted by such in silico molecular design methods. Additional quantum chemical calculations offer, together with the crystal structure analysis, insight into the role of spin-passive structural components. A thermodynamic analysis based on an Ising-like mean field model (Slichter-Drickammer approximation) provides estimates of the enthalpy, entropy and cooperativity of the crossover between the high and low spin states.

Chemical analysis of a marine-derived fungus, Chaunopycnis sp. (CMB-MF028), isolated from the inner tissue of a pulmonate false limpet Siphonaria sp., collected from rock surfaces in the intertidal zone of Moora Park, Shorncliffe, Queensland, yielded the tetramic acid F-14329 (1) and new analogues, chaunolidines A-C (2-4), together with the new pyridinone chaunolidone A (5), and pyridoxatin (6). Structures inclusive of absolute configurations were assigned to 1-6 on the basis of detailed spectroscopic analysis, X-ray crystallography, electronic circular dichroism (ECD), biosynthetic considerations and chemical interconversion. Chaunolidine C (4) exhibits modest Gram-positive antibacterial activity (IC50 5-10 μM), while chaunolidone A (5) is a selective and potent inhibitor (IC50 0.09 μM) of human non-small cell lung carcinoma cells (NCI-H460). Tetramic acids 1-4 form metal chelates with Fe(III), Al(III), Cu(II), Mg(II) and Zn(II).

Microbial electrosynthesis is a highly promising application of microbial electrochemical technologies for the sustainable production of organic compounds. At the same time a multitude of questions need to be answered and challenges to be met. Central for its further development is using appropriate electroactive microorganisms and their efficient extracellular electron transfer (EET) as well as wiring of the metabolism to EET. Among others, Clostridia are believed to represent electroactive microbes being highly promising for microbial electrosynthesis. We investigated the potential steps and challenges for the bio-electrochemical fermentation (electro-fermentation) of mid-chain organic acids using Clostridium kluyveri. Starting from a metabolic model the potential limitations of the metabolism as well as beneficial scenarios for electrochemical stimulation were identified and experimentally investigated. C. kluyveri was shown to not be able to exchange electrons with an electrode directly. Therefore, exogenous mediators (2-hydroxy-1,4-naphthoquinone, potassium ferrocyanide, neutral red, methyl viologen, methylene blue, and the macrocyclic cobalt hexaamine [Co(trans-diammac)]3+) were tested for their toxicity and electro-fermentations were performed in 1L bioreactors covering 38 biotic and 8 abiotic runs. When using C. kluyveri and mediators, maximum absolute current densities higher than the abiotic controls were detected for all runs. At the same time, no significant impact on the cell metabolism (product formation, carbon recovery, growth rate) was found. From this observation, we deduce general potential limitations of electro-fermentations with C. kluyveri and discuss strategies to successfully overcome them.

The present work reports on the synthesis, anti-Trypanosoma cruzi activities and docking studies of a novel series of 2-(pyridin-2-yl)-1,3-thiazoles derived from 2-pyridine thiosemicarbazone. The majority of these compounds are potent cruzain inhibitors and showed excellent inhibition on the trypomastigote form of the parasite, and the resulting structure-activity relationships are discussed. Together, these data present a novel series of thiazolyl hydrazones with potential effects against Chagas disease and they could be important leads in continuing development against Chagas disease.

Development of peptide-based drugs has been severely limited by lack of oral bioavailability with less than a handful of peptides being truly orally bioavailable, mainly cyclic peptides with N-methyl amino acids and few hydrogen bond donors. Here we report that cyclic penta- and hexa-leucine peptides, with no N-methylation and five or six amide NH protons, exhibit some degree of oral bioavailability (4-17%) approaching that of the heavily N-methylated drug cyclosporine (22%) under the same conditions. These simple cyclic peptides demonstrate that oral bioavailability is achievable for peptides that fall outside of rule-of-five guidelines without the need for N-methylation or modified amino acids.

Attempted synthesis of the imidazylate derivative of 1,2-O-isopropylidene- α-D-glucurono-6,3-lactone (2) via treatment with sulfuryl chloride in the presence of excess imidazole in DMF at either -40°C or -70°C resulted in the unexpected formation of 5-chloro-5-deoxy-1,2-O-isopropylidene-β-l- idurono-6,3-lactone (7). Chloride 7 presumably forms via the rapid S N2 displacement by a chloride ion of an initially formed chlorosulfate ester intermediate, which is evidently unusually reactive. The identity of the product was confirmed by a single-crystal X-ray structure determination.

The oxidation of cineole to (1 R )-6β-hydroxycineole by cytochrome P450 cin (CYP176A) is utilised as the initial step in the synthesis of a range of compounds, both novel and ones previously known only as racemates. The potential of P450 cin to provide useful, enantiopure building blocks is thus demonstrated. In particular, hydroxylation by this enzyme was used as the initial step in the synthesis of a range of functionalised cineole derivatives that could be used as mechanistic probes to elucidate the effect of substrate structure on the transformations mediated by P450 cin .

Inhibition of mushroom tyrosinase was observed with synthetic dihydropyrano[3,2-b]chromenediones. Among them, DHPC04 displayed the most potent tyrosinase inhibitory activity with a Ki value of 4μM, comparable to the reference standard inhibitor kojic acid. A kinetic study suggested that these synthetic heterocyclic compounds behave as competitive inhibitors for the L-DOPA binding site of the enzyme. Furthermore, molecular modeling provided important insight into the mechanism of binding interactions with the tyrosinase copper active site.

The commercial antibiotics tetracycline (3), minocycline (4), chlortetracycline (5), oxytetracycline (6), and doxycycline (7) were biotransformed by a marine-derived fungus Paecilomyces sp. to yield seco-cyclines A–H (9–14, 18 and 19) and hemi-cyclines A–E (20–24). Structures were assigned by detailed spectroscopic analysis, and in the case of 10 X-ray crystallography. Parallel mechanisms account for substrate-product specificity, where 3–5 yield seco-cyclines and 6 and 7 yield hemi-cyclines. The susceptibility of 3–7 to fungal biotransformation is indicative of an unexpected potential for tetracycline “degradation” (i.e., antibiotic resistance) in fungal genomes. Significantly, the fungal-derived tetracycline-like viridicatumtoxins are resistant to fungal biotransformation, providing chemical insights that could inform the development of new tetracycline antibiotics resistant to enzymatic degradation.

The 19-nor-clerodanes are compact, densely functionalized diterpenes based on a stereocentre-rich decalin scaffold. To date only a few examples of the 19-nor-clerodanes have been synthesized, hence new flexible strategies are required. We herein describe the stereocontrolled construction of the cis-hydroxy decalin core in a concise fashion.

The absolute stereochemistry of the steroidal saponins bethosides B and C was previously assigned as (22R,25R) on the basis of work that employed Horeau's method. Our studies of helosides A and B created doubt about both the original assignment and consequently our conclusion that relied upon it. The absolute configurations of bethosides B and C are revised to (22S,25R) following X-ray crystallographic analysis of their aglycone. Synthesis and full spectral characterization of both the 22R and 22S aglycones is reported to facilitate future stereochemical assignments in this series of saponins.