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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.

The oxygen-tolerant and molybdenum-dependent formate dehydrogenase FdsDABG from Cupriavidus necatoris capable of catalyzing both formate oxidation to CO2and the reverse reaction (CO2reduction 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 CO2reduction 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 (IC50: 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 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 (CuI) and dormant (CuII) 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 BrCH2CN to release •CH2CN radicals when in complex with CuI. Moreover, the [CuI(L1)]+complex can capture the •CH2CN radical to form a new species [CuII(L1)(CH2CN)]+in situthat, on reduction, exhibits halogen atom transfer reactivity 3 orders of magnitude greater than its parent complex [CuI(L1)]+. This unprecedented rate acceleration has been identified by electrochemistry, successfully reproduced by simulation, and exploited in a Cu-catalyzed bulk electrosynthesis where [CuII(L1)(CH2CN)]+participates as a radical donor in the atom transfer radical addition of BrCH2CN to a selection of styrenes. The formation of these turbocharged catalysts in situduring 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 this work, the Na3[Ln(ODA)3]·2NaClO4·6H2O (Ln = Ce–Yb; ODA = oxydiacetate) series was analyzed with the ab initioligand 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.

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 vitroand in vivoprofiles of a new bicyclic nitroimidazole subclass, namely, nitroimidazopyrazinones, against mycobacteria and Trypanosoma cruzi. Derivatives with monocyclic side chains were selective against Mycobacterium tuberculosisand 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 (73and 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.

Chemical investigation of Australian pasture plant-derived Streptomycessp. 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 15facilitating 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 5to 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 1–13and the semisynthetic analogues 14and 21–26revealed 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 (IC500.2–1.6 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.

Chemical investigations into solid phase cultivations of an Australian sheep station pasture plant derived Streptomycessp. 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 1and 2resolved 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 1–8and 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.

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.

The evidence for the existence of metal complexes containing H3O+as a ligand in the solid state is examined. Each of the 68 examples in the Cambridge Structural Database in which H3O+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 H3O+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 H3O+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.

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

Dysphaniais 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 bioactivity investigation of native Dysphaniahas been performed. Herein reported is the isolation and elucidation of (6E,9E)-zerumbone epoxide and a hitherto unreported isomer, (6Z,9E)-zerumbone epoxide, from D. kalpari. In addition, a novel isodaucane sesquiterepene, kalparinol, was isolated from both D. kalpariand D. rhadinostachya. The coisolation of the humulene and isodaucane skeletons, combined with the lack of any cadalane systems, could suggest an alternate novel biogenetic pathway originating from zerumbone, which is unlike any other proposals for the isodaucene system.

A GNPS molecular networking approach mapped a library of 960 southern Australian marine sponges and prioritized Dysideasp. (CMB-01171) for chemical investigation. Although the published natural products literature on Australian Dysideasponges extends back over half a century and suffers from the perception of being near exhausted, fractionation of Dysideasp. (CMB-01171) led to the discovery of a family of 10 new biosynthetically and chemically related sesquiterpenes. Detailed spectroscopic analysis guided structure elucidation identified dysidealactams A–F (1–6), dysidealactones A and B (7and 8), and two solvolysis artifacts, 9and 10. The dysidealactams A–D (1–4) incorporate a rare glycinyl-lactam functionality, while dysidealactam E (5) is particularly noteworthy in incorporating an unprecedented glycinyl-imide moiety. In addition to expanding knowledge of Dysideanatural products, this study demonstrates the value of applying GNPS molecular networking to map chemical diversity and prioritize the selection of marine sponge extracts for more detailed chemical analysis.

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 palustrisHaA2, 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.

Chemical analysis of the fungus Chrysosporiumsp. CMB-F294 isolated from the gastrointestinal tract of a market-purchased specimen of Mugilmullet 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).