Global (Q)SARs for skin sensitisation–assessment against OECD principles‖

As part of a European Chemicals Bureau contract relating to the evaluation of (Q)SARs for toxicological endpoints of regulatory importance, we have reviewed and analysed (Q)SARs for skin sensitisation. Here we consider some recently published global (Q)SAR approaches against the OECD principles and present re-analysis of the data. Our analyses indicate that “statistical” (Q)SARs which aim to be global in their applicability tend to be insufficiently robust mechanistically, leading to an unacceptably high failure rate. Our conclusions are that, for skin sensitisation, the mechanistic chemistry is very important and consequently the best non-animal approach currently applicable to predict skin sensitisation potential is with the help of an expert system. This would assign compounds into mechanistic applicability domains and apply mechanism-based (Q)SARs specific for those domains and, very importantly, recognise when a compound is outside its range of competence. In such situations, it would call for human expert input supported by experimental chemistry studies as necessary.     

Do complex matrices modify the sorptive properties of polydimethylsiloxane (PDMS) for non-polar organic chemicals?

The partitioning of non-polar analytes into the silicone polydimethylsiloxane (PDMS) is the basis for many analytical approaches such as solid phase microextraction (SPME), stir bar sorptive extraction (SBSE) and environmental passive sampling. Recently, the methods have been applied to increasingly complex sample matrices. The present work investigated the possible effect of complex matrices on the sorptive properties of PDMS. First, SPME fibers with a 30 μm PDMS coating were immersed in 15 different matrices, including sediment, suspensions of soil and humic substances, mayonnaise, meat, fish, olive oil and fish oil. Second, the surface of the fibers was wiped clean, and together with matrix-free control fibers, they were exposed via headspace to 7 non-polar halogenated organic chemicals in spiked olive oil. The fibers were then solvent-extracted, analyzed, and the ratios of the mean concentrations in the matrix-immersed fibers to the control fibers were determined for all matrices. These ratios ranged from 92% to 112% for the four analytes with the highest analytical precision (i.e. polychlorinated biphenyls (PCBs) 3, 28, 52 and brominated diphenyl ether (BDE) 3), and they ranged from 74% to 133% for the other three compounds (i.e. PCBs 101, 105 and γ-hexachlorocyclohexane (HCH)). We conclude that, for non-polar, hydrophobic chemicals, the sorptive properties of the PDMS were not modified by the diverse investigated media and consequently that PDMS is suited for sampling of these analytes even in highly complex matrices.     

Chlorine adsorption on Au(111): chlorine overlayer or surface chloride?

We report the first scanning tunneling microscope (STM) investigation, combined with density functional theory calculations, to resolve controversy regarding the bonding and structure of chlorine adsorbed on Au(111). STM experiments are carried out at 120 K to overcome instability caused by mobile species upon chlorine adsorption at room temperature. Chlorine adsorption initially lifts the herringbone reconstruction. At low coverages (<0.33 ML), chlorine binds to the top of Au(111)-(1 x 1) surface and leads to formation of an overlayer with (square root(3) x square root(3))R30 degree structure at 0.33 ML. At higher coverages, packing chlorine into an overlayer structure is no longer favored. Gold atoms incorporate into a complex superlattice of a Au-Cl surface compound.     

Trans-(−)-Kusunokinin: A Potential Anticancer Lignan Compound against HER2 in Breast Cancer Cell Lines?

Trans-(−)-kusunokinin, an anticancer compound, binds CSF1R with low affinity in breast cancer cells. Therefore, finding an additional possible target of trans-(−)-kusunokinin remains of importance for further development. Here, a computational study was completed followed by indirect proof of specific target proteins using small interfering RNA (siRNA). Ten proteins in breast cancer were selected for molecular docking and molecular dynamics simulation. A preferred active form in racemic trans-(±)-kusunokinin was trans-(−)-kusunokinin, which had stronger binding energy on HER2 trans-(+)-kusunokinin; however, it was weaker than the designed HER inhibitors (03Q and neratinib). Predictively, trans-(−)-kusunokinin bound HER2 similarly to a reversible HER2 inhibitor. We then verified the action of (±)-kusunokinin compared with neratinibon breast cancer cells (MCF-7). (±)-Kusunokinin exhibited less cytotoxicity on normal L-929 and MCF-7 than neratinib. (±)-Kusunokinin and neratinib had stronger inhibited cell proliferation than siRNA-HER2. Moreover, (±)-kusunokinin decreased Ras, ERK, CyclinB1, CyclinD and CDK1. Meanwhile, neratinib downregulated HER, MEK1, ERK, c-Myc, CyclinB1, CyclinD and CDK1. Knocking down HER2 downregulated only HER2. siRNA-HER2 combination with (±)-kusunokinin suppressed HER2, c-Myc, CyclinB1, CyclinD and CDK1. On the other hand, siRNA-HER2 combination with neratinib increased HER2, MEK1, ERK, c-Myc, CyclinB1, CyclinD and CDK1 to normal levels. We conclude that trans-(±)-kusunokinin may bind HER2 with low affinity and had a different action from neratinib.     

Au dimers on thin MgO(001) films: flat and charged or upright and neutral?

A combination of low temperature scanning tunneling microscopy (STM) and theoretical calculations is used to investigate Au dimers, supported on thin MgO(001) films, whose thickness was chosen such that charge transfer from the Ag substrate to the deposited Au is possible. Au dimers exist not only in an upright geometry--as theoretically predicted to be the most stable configuration--but also as flat lying dimers which populate a manifold of different azimuthal orientations. Apart from the difference in adsorption configurations, these two isomers exhibit rather different electronic structures: while upright dimers are neutral, flat ones are charged.     

Theoretical study on molecular property of protactinium(V) and uranium(VI) oxocations: why does protactinium(V) form monooxo cations in aqueous solution?

The stability of Pa(V) and U(VI) oxocations in aqueous solution were theoretically investigated by means of density functional theory calculations. As a result, the present calculations clearly supported an experimental result from an energetic point of view that monooxo protactinyl cation, PaO3+, is a preferable species for Pa(V) in aqueous solution, although dioxo protactinyl cation, PaO2+, is not a feasible form. By an analysis of molecular orbitals, we revealed that 6d orbitals of Pa(V) destabilize the pi orbitals of PaO2+, because 6d-2p antibonding orbital conflicts with another 5f-2p bonding orbital. For stable dioxo uranyl cation, UO2(2+), we found that 6d orbitals of U(VI), in contrast, form a bonding orbital with the 2p orbitals, and this bonding orbital coexists at an angle with the 5f-2p bonding orbital due to an electron correlation.     

IrII(ethene): metal or carbon radical?

One-electron oxidation of [(Me(n)tpa)Ir(I)(ethene)]+ complexes (Me(3)tpa = N,N,N-tri(6-methyl-2-pyridylmethyl)amine; Me(2)tpa = N-(2-pyridylmethyl)-N,N,-di[(6-methyl-2-pyridyl)methyl]-amine) results in relatively stable, five-coordinate Ir(II)-olefin species [(Me(n)tpa)Ir(II)(ethene)](2+) (1(2+): n = 3; 2(2+): n = 2). These contain a "vacant site" at iridium and a "non-innocent" ethene fragment, allowing radical type addition reactions at both the metal and the ethene ligand. The balance between metal- and ligand-centered radical behavior is influenced by the donor capacity of the solvent. In weakly coordinating solvents, 1(2+) and 2(2+) behave as moderately reactive metallo-radicals. Radical coupling of 1(2+) with NO in acetone occurs at the metal, resulting in dissociation of ethene and formation of the stable nitrosyl complex [(Me(3)tpa)Ir(NO)](2+) (6(2+)). In the coordinating solvent MeCN, 1(2+) generates more reactive radicals; [(Me(3)tpa)Ir(MeCN)(ethene)](2+) (9(2+)) by MeCN coordination, and [(Me(3)tpa)Ir(II)(MeCN)](2+) (10(2+)) by substitution of MeCN for ethene. Complex 10(2+) is a metallo-radical, like 1(2+) but more reactive. DFT calculations indicate that 9(2+) is intermediate between the slipped-olefin Ir(II)(CH(2)=CH(2)) and ethyl radical Ir(III)-CH(2)-CH(2). resonance structures, of which the latter prevails. The ethyl radical character of 9(2+) allows radical type addition reactions at the ethene ligand. Complex 2(2+) behaves similarly in MeCN. In the absence of further reagents, 1(2+) and 2(2+) convert to the ethylene bridged species [(Me(n)tpa)(MeCN)Ir(III)(mu(2)-C(2)H(4))Ir(III)(MeCN)(Me(3)tpa)](4+) (n = 3: 3(4+); n = 2: 4(4+)) in MeCN. In the presence of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxo), formation of 3(4+) from 1(2+) in MeCN is completely suppressed and only [(Me(3)tpa)Ir(III)(TEMPO(-))(MeCN)](2+) (7(2+)) is formed. This is thought to proceed via radical coupling of TEMPO at the metal center of 10(2+). In the presence of water, hydrolysis of the coordinated acetonitrile fragment of 7(2+) results in the acetamido complex [(Me(3)tpa)Ir(III)(NHC(O)CH(3)))(TEMPOH)](2+) (8(2+)).     

(Iso)Quinoline–Artemisinin Hybrids Prepared through Click Chemistry: Highly Potent Agents against Viruses

Viral infections cause life-threatening diseases in millions of people worldwide every year and there is an urgent need for new, effective antiviral drugs. Hybridization of two chemically diverse compounds into a new bioactive effector product is a successful concept to improve the properties of a hybrid drug relative to the parent compounds. In this study, (iso)quinoline–artemisinin hybrids, obtained through copper-catalyzed azide–alkyne cycloaddition or metal-free click reactions (in organic solvents or in the presence of water), were analyzed in vitro, for the first time, for their inhibitory activity against human cytomegalovirus (HCMV), relative to their parent compounds and the reference drug ganciclovir. EC₅₀ (HCMV) values were obtained in a range 0.22–1.20 μm , which indicated highly potent antiviral properties in the absence of cytotoxic effects on normal cells (CC₅₀>100 μm ). The most active hybrid, 1 (EC₅₀=0.22 μm ), is 25 times more potent than its parent compound artesunic acid (EC₅₀=5.41 μm ) and 12 times more efficient than the standard drug ganciclovir (EC₅₀=2.6 μm ). Interestingly, hybrid 1 also shows inhibitory activity against hepatitis B virus in vitro (EC₅₀ (HBeAg)=2.57 μm ).     

ChemInform Abstract: Are Cyclogallenes (M2(GaH)3) (M: Li,Na, K) Aromatic?

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.     

Structure-based modelling in reproductive toxicology: (Q)SARs for the placental barrier†

The replacement of animal testing for endpoints such as reproductive toxicity is a long-term goal. This study describes the possibilities of using simple (quantitative) structure-activity relationships ((Q)SARs) to predict whether a molecule may cross the placental membrane. The concept is straightforward, if a molecule is not able to cross the placental barrier, then it will not be a reproductive toxicant. Such a model could be placed at the start of any integrated testing strategy. To develop these models the literature was reviewed to obtain data relating to the transfer of molecules across the placenta. A reasonable number of data were obtained and are suitable for the modelling of the ability of a molecule to cross the placenta. Clearance or transfer indices data were sought due to their ability to eliminate inter-placental variation by standardising drug clearance to the reference compound antipyrine. Modelling of the permeability data indicates that (Q)SARs with reasonable statistical fit can be developed for the ability of molecules to cross the placental barrier membrane. Analysis of the models indicates that molecular size, hydrophobicity and hydrogen-bonding ability are molecular properties that may govern the ability of a molecule to cross the placental barrier.     

Room temperature bilayer water structures on a rutile TiO2(110) surface: hydrophobic or hydrophilic?

The lack of understanding of the molecular-scale water adsorbed on TiO₂ surfaces under ambient conditions has become a major obstacle for solving the long-time scientific and applications issues, such as the photo-induced wetting phenomenon and designing novel advanced TiO₂-based materials. Here, with the molecular dynamics simulation, we identified an ordered water bilayer structure with a two-dimensional hydrogen bonding network on a rutile TiO₂(110) surface at ambient temperature, corroborated by vibrational sum-frequency generation spectroscopy. The reduced number of hydrogen bonds between the water bilayer and water droplet results in a notable water contact angle (25 ± 5°) of the pristine TiO₂ surface. This surface hydrophobicity can be enhanced by the adsorption of the formate/acetate molecules, and diminishes with dissociated H₂O molecules. Our new physical framework well explained the long-time controversy on the origin of the hydrophobicity/hydrophilicity of the TiO₂ surface, thus help understanding the efficiency of TiO₂ devices in producing electrical energy of solar cells and the photo-oxidation of organic pollutants.

An ordered water bilayer structure was identified on a rutile TiO₂(110) surface at ambient temperature by combining VSFG experiments and MD simulations, which well explained the long-time controversy on the wetting behaviors of the TiO₂ surface.