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The aerial parts of the endemic Australian plant Eremophila debilis (Myoporaceae) contain 3% dry weight of the biologically active 5,6,7,3',4',5'-hexamethoxyflavone, which had its structured confirmed using X-ray crystal crystallography. The presence of significant levels of the polypharmacologically active 5,6,7,3',4',5'-hexamethoxyflavone in the edible parts of the plant has potential implications for its use as a food and bush medicine.

This article outlines the synthesis of an electrophilic organoruthenium carboxylic acid of the structure [(η5-Cp*)Ru(η6-C6H5CO2H)]+ and explores the behavior of this molecule under a variety of nucleophilic substitution conditions using a range of oxygen and nitrogen based nucleophiles including alcohols, primary and secondary amines and aromatic sulfonamides. The resulting organoruthenium ester [(η5-Cp*)Ru(η6-C6H5COOR)]+ and amide [(η5-Cp*)Ru(η6-C6H5CONHR)]+ or [(η5-Cp*)Ru(η6-C6H5CONR)]+ complexes are additionally reported. All prepared complexes have been fully characterized using Fourier-transform IR and NMR spectroscopy and electrospray mass spectrometry with single-crystal X-ray structural determinations reported for three complexes: 3[(η5-Cp*)Ru(η6-C6H5CO2H)]B(C6H5)4.[(η5-Cp*)Ru(η6-C6H5CO2)].H2O, [(η5-Cp*)Ru(η6-C6H5CONHCH2Ph)]PF6 and [(η5-Cp*)Ru(η6-C6H5CONHSO2C6H4COMe)]PF6. Complexes were also evaluated for in vitro cytotoxic activity against the MCF7 (hormone-dependant breast cancer), MDA-MD-231 (hormone-independent breast cancer), MM96L (human melanoma) tumourigenic cell lines and the normal NFF (neonatal foreskin fibroblasts) human cell line.

The 5-nitrosalicylate ester of 2-acetamidophenylboronic acid (C15H10BN2O6) is formed under crystallization conditions from the 5-nitrosalicylate ester of 2-aminophenylboronic acid. The boron at the center of this structure exists as a tetrahedral complex produced by a dative bond with the amide carbonyl. The perpendicular shape produces an unusual packing structure including a bifurcated hydrogen bond between the amide hydrogen and carbonyl groups on two neighboring molecules. We propose that this reaction occurs due to increased Lewis acidity of the nitrosalicylate ester of 2-aminophenylboronic acid.

The title compounds [(Ph3As)2AuI] and [(Ph3As)3AuI] have been crystallized from equimolar solutions of Bu4NAuI2 and AsPh3 in dimethylformamide and structurally characterized by single crystal X-ray diffraction studies. [(Ph3As)2AuI] crystallizes in space group C2/c, Z 4, and is isomorphous with other [(Ph3E)2MX] (MX=coinage metal(i) salt) arrays, with the Au–I bond being disposed on a crystallographic 2-axis: Au–I, As 2.7008(2), 2.4337(2) Å, As–Au–As, I 125.736(8)°, 117.132(4)° (153K). [(Ph3As)3AuI] crystallizes as a triclinic phase in space group , Z 4, and is isomorphous with [(Ph3Sb)3CuI] and [(Ph3P)3AgI]: Au–As 2.4847–2.5049(10), Au–I 2.8518(8), 2.8597(7) Å with As–Au–As, I 109.67(3)–115.97(3)°, 101.33(2)–106.85(3)°. A second ‘[(Ph3As)3AuI]’ product was obtained as a co-crystalline phase in space group P21/n containing [(Ph3As)3AuI], and [(Ph3As)2AuI] accompanied by an additional unbound Ph3As molecule, i.e. [(Ph3As)3AuI]·[(Ph3As)2AuI·Ph3As], with structural parameters closely similar to those for the corresponding separate [(Ph3As)3AuI] and [(Ph3As)2AuI] complexes described above. Comparison of the bond lengths for these and related complexes show that they are generally consistent with the ‘gold is smaller than silver’ phenomenon caused by relativistic orbital contraction effects in gold, but the results also show that the magnitude of this effect is dependent on the nature of the metal–ligand bonds involved, and on changes in the metal coordination environment, which can in some circumstances yield trends in which the effect on particular bonds is partially masked or even reversed.

Neutral mononuclear molecular silver(i) carboxylate complexes of the form [(Ph3P)2Ag(O2XY)] with O2XY=O2CCH2Ph, O2CCHPh2, O2CC(CH3)3, O2CCH2C(CH3)3, and O2CCF3 (compounds 1–4 and 5β) have been investigated in the solid state using single-crystal X-ray structure determinations, 1D 31P CPMAS NMR and 2D 31P–31P CPCOSY NMR measurements, and ab initio computational modelling. The results show that these complexes contain P2AgO2 molecular cores with four-coordinate silver in which the carboxylate ligands are weakly bound to the silver atoms via the two oxygen atoms giving rise to unsymmetrical chelate units. Crystal structure determinations and solid-state NMR spectra have also been analysed for the mononuclear molecular silver(i) nitrate complex [(Ph3P)2Ag(O2NO)] (9α) and two polymorphs of its toluene monosolvate (11α, β). In 9α, the two PPh3 ligands are of the same chirality, whereas in 11α, β, they are opposed. The crystalline environments in the polymorphs have been explored by way of Hirshfeld surface analyses, after quantum-mechanical isolated-molecule calculations had shown that although the molecular energies of the experimental geometries of 9α, and 11α, β are significantly different from each other and from the energies of the optimized geometries, the latter, in contrast, do not differ significantly from each other despite the conformational isomerism. It has further been shown using 9α as an example that the energy dependence on variation of the P–Ag–P angle over a range of ~15° is only ~5 kJ mol−1. All this indicates that the forces arising from crystal packing result in significant perturbations in the experimental geometries, but do not alter the stereoisomerism caused by the donor atom array around the Ag atom. In the NMR study, a strong inverse correlation has been found between 1J(107/109Ag,31P) and the Ag–P bond length across all carboxylate and nitrate compounds.

Modern beer production is a complex industrial process. However, some of its biochemical details remain unclear. Using mass spectrometry proteomics, we have performed a global untargeted analysis of the proteins present across time during nano-scale beer production. Samples included sweet wort produced by a high temperature infusion mash, hopped wort, and bright beer. This analysis identified over 200 unique proteins from barley and yeast, emphasizing the complexity of the process and product. We then used data independent SWATH-MS to quantitatively compare the relative abundance of these proteins throughout the process. This identified large and significant changes in the proteome at each process step. These changes described enrichment of proteins by their biophysical properties, and identified the appearance of dominant yeast proteins during fermentation. Altered levels of malt modification also quantitatively changed the proteomes throughout the process. Detailed inspection of the proteomic data revealed that many proteins were modified by protease digestion, glycation, or oxidation during the processing steps. This work demonstrates the opportunities offered by modern mass spectrometry proteomics in understanding the ancient process of beer production.

Bioassay-guided fractionation of an antimalarial DCM/MeOH extract derived from the Australian rainforest fungus Entonaema sp. resulted in the isolation of three new isoindolinone derivatives, entonalactams A–C (1–3), along with the known natural products 3-methoxy-5-methylbenzene-1,2-diol (4), daldinal B (5), and ergosta-4,6,8(14),22-tetraen-3-one (6). The chemical structures of the new secondary metabolites were determined following extensive 1D/2D NMR and MS data analysis. A single crystal X-ray structure for entonalactam A (1) confirmed the NMR-based structure assignment. Entonalactams A–C (1–3) were all determined to be racemic based on chiro-optical data. All secondary metabolites were tested in vitro against Plasmodium falciparum malaria parasites, and ergosta-4,6,8(14),22-tetraen-3-one (6) was identified as the most active compound with 66% inhibition at 50 μM.

The fungal metabolite 3-chloro-4-hydroxyphenylacetic acid (1) was utilized in the generation of a unique drug-like screening library using parallel solution-phase synthesis. A 20-membered amide library (3-22) was generated by first converting 1 to methyl (3-chloro-4-hydroxyphenyl)acetate (2), then reacting this scaffold with a diverse series of primary amines via a solvent-free aminolysis procedure. The structures of the synthetic analogues (3-22) were elucidated by spectroscopic data analysis. The structures of compounds 8, 12, and 22 were confirmed by single X-ray crystallographic analysis. All compounds were evaluated for cytotoxicity against a human prostate cancer cell line (LNCaP) and for antiparasitic activity toward Trypanosoma brucei brucei and Plasmodium falciparum and showed no significant activity at 10 μM. The library was also tested for effects on the lipid content of LNCaP and PC-3 prostate cancer cells, and it was demonstrated that the fluorobenzyl analogues (12-14) significantly reduced cellular phospholipid and neutral lipid levels.

Eight new dihydro-β-agarofurans, denhaminols A-H (1-8), were isolated from the leaves of the Australian rainforest tree Denhamia celastroides. The chemical structures of 1-8 were elucidated following analysis of 1D/2D NMR and MS data. The absolute configuration of denhaminol A (1) was determined by single-crystal X-ray crystallography. All compounds were evaluated for cytotoxic activity against the human prostate cancer cell line LNCaP, using live-cell imaging and metabolic assays. Denhaminols A (1) and G (7) were also tested for their effects on the lipid content of LNCaP cells. This is the first report of secondary metabolites from D. celastroides.

A series of amide (8–32, 40–45) and urea (33, 34, 36–39) analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine- and mefloquine-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast cells (selectivity index100). Two of these compounds, 8 and 33, exhibited good aqueous solubility and metabolic stability, and when administered subcutaneously to mice (32 mg kg(-1)), plasma concentrations remained above 0.2 μM for at least 8 h. Both 8 and 33 were well tolerated in mice after subcutaneous administration of 32 mg kg(-1) twice daily for 4 days. Using this regimen blood stage P. berghei was suppressed by 52% for 8 and 26% for 33, relative to the vehicle control.

This chapter presents a theoretical review and analysis of the development of hyperkinesis as a medical diagnosis. It describes the diagnosis, reviews the pertinent literature relevant to its development, and also presents a sociological analysis of its discovery. In developing an analysis of the discovery of hyperkinesis it is useful to divide the relevant factors into those that might be considered clinical factors and social factors. The social factors affecting the discovery of hyperkinesis can be divided into three areas: the pharmaceutical revolution, trends in the medical profession; and government action. The chapter discusses the three issues: how children's deviant behavior became conceptualized as a medical problem, why this occurred when it did, and what are some of the implications of the medicalization of deviant behavior. The discovery of hyperkinesis highlights important sociological question: Does the invention or discovery of new forms of medical social control lead to new medical labels.

Single crystal X-ray structure determinations are recorded for diphenyl(2-formylphenyl)phosphine gold(I) halides [Ph 2 (Ph-CHO)PAuX], X = Cl, Br and I, and for redeterminations of enhanced precision for triphenylphosphine gold(I) halides [Ph 3 PAuX], X = Cl, Br, I, and SCN 0.91 Br 0.09 . These complexes, other than [Ph 2 (Ph-CHO)PAuCl], together with a diverse array of other structures, crystallize as an isomorphous series in the orthorhombic space group P 2 1 2 1 2 1 a = 9.804(1)–11.906(3), b = 11.771(2)–12.996(3) and c = 12.871(1)–14.169(3) A. In these complexes, introduction of the formyl group results in only minor differences between the conformations of the two phosphine ligands and the corresponding Au–P, Au–X, and Au–P–X bond lengths and angles. The crystal packings of [Ph 3 PAuX] for X = Cl, Br, I and of [Ph 2 (Ph-CHO)PAuX] for X = Br and I show that, while these structures are isomorphous, different supramolecular synthons may be present, suggesting global packing considerations are all-important rather than specific supramolecular interactions. This is borne out by the different packing found for the centrosymmetric [Ph 2 (Ph-CHO)PAuCl] structure. Crystallization of the mixed anion structure [Ph 3 PAuSCN 0.91 Br 0.09 ] in the above P 2 1 2 1 2 1 lattice rather than the P 2 1 /c lattice reported for pure [Ph 3 PAuSCN] suggests that co-crystallization with bromide may impose constraints on packing considerations which favor crystallization in the P 2 1 2 1 2 1 lattice.

An improved and versatile synthesis of tafuramycin A, a potent anticancer and parasite-attenuating agent, is reported. The three major improvements that optimized yield, simplified purification and allowed the synthesis of more versatile duocarmycin analogues are: a first-time reported regioselective bromination using DMAP as catalyst; the control of the aryl radical alkene cyclization step to prevent the dechlorination side reaction; and the design of a new protection/deprotection method to avoid furan double bond reduction during the classical O-benzyl deprotection in the final step. This alternative protection/deprotection strategy provides ready access to duocarmycin seco-analogues that carry labile functionalities under reducing reaction conditions. Tafuramycin A (3) was prepared in either 8 steps from intermediate 6 or 7 steps from intermediate 17 in 52% or 37% yield respectively. Our strategy provides a significant improvement on the original procedure (11% overall yield) and greater versatility for analogue development.

Glycogen Phosphorylase (GP) is a functionally active dimeric enzyme, which is a target for inhibition of the conversion of glycogen to glucose-1-phosphate. In this study we report the design and synthesis of 14 new pyridone derivatives, and seek to extend the SAR analysis of these compounds. The SAR revealed the minor influence of the amide group, importance of the pyridone ring both spatially around the pyridine ring and for possible π-stacking, and confirmed a preference for inclusion of 3,4-dichlorobenzyl moieties, as bookends to the pyridone scaffold. Upon exploring a dimer strategy as part of the SAR analysis, the first extended 2-oxo-dihydropyridinyl-3-yl amide nanomolar based inhibitors of GPa (IC50 = 230 and 260 nM) were identified.

Chemical investigations of the CH2Cl2 extract obtained from the leaves of the Australian rainforest tree Maytenus bilocularis afforded three new dihydro-β-agarofurans, bilocularins A-C (1-3), and six known congeners, namely, celastrine A (4), 1α,6β,8α-triacetoxy-9α-benzoyloxydihydro-β-agarofuran (5), 1α,6β-diacetoxy-9α-benzoyloxy-8α-hydroxydihydro-β-agarofuran (6), Ejap-10 (11), 1α,6β-diacetoxy-9β-benzoyloxydihydro-β-agarofuran (12), and Ejap-2 (13). The major compound 1 was used in semisynthetic studies to afford four ester derivatives (7-10). The chemical structures of 1-3 were elucidated following analysis of 1D/2D NMR and MS data. The absolute configurations of bilocularins A (1) and B (2) were determined by single-crystal X-ray diffraction analysis. All compounds were evaluated for cytotoxic activity against the human prostate cancer cell line LNCaP; none of the compounds were active. However, several compounds showed similar potency to the drug efflux pump inhibitor verapamil in reversing the drug resistance of the human leukemia CEM/VCR R cell line. In addition, similar to verapamil, compound 5 was found to inhibit leucine uptake in LNCaP cells (IC50 = 15.5 μM), which was more potent than the leucine analogue 2-aminobicyclo[2.2.1]heptane-2-carbocyclic acid. This is the first report of secondary metabolites from Maytenus bilocularis.