Experiences with the Application of QSAR in the Routine of the Notification Procedure

Abstract

On behalf of the Umweltbundesamt the Fraunhofer Gesellschaft has developed a software system (SAR-system) comprising more than 90 estimation models for endpoints relevant in environmental risk assessment. These estimation models are based on the approach of quantitative structure-activity relationships (QSAR). All models were checked for their validity and application range. In the last months the Umweltbundesamt started to test the applicability of some models concerning the endpoints fish acute toxicity, daphnia acute toxicity and ready (i.e., ultimate) biodegradability in the daily routine of the notification procedure. For testing these models the corresponding confidential data given in the dossiers of substances notified 1993 in Germany, were used. We were able to make calculations for 36% of the notified substances. For the remaining 64% of the chemicals it was impossible to accomplish SAR estimations due to several reasons, e.g., ionic structure of the compounds. Different results for the applicability of the mentioned endpoints are obtained. The predictions of the fish and Daphnia toxicity are in sufficient agreement with the experimental results, in case of the fish toxicity we receive 58% agreement, for the Daphnia toxicity 56% The corresponding values which were obtained in the US EPA/E.C. Joint Project on the evaluation of (quantitative) structure activity relationships were 82.3% and 70.9% About 300 different models were used for the calculations of these endpoints within the framework of the EPA/EC project. The SAR-system presented here contains 8 models for estimating the fish toxicity and 6 models for the Daphnia toxicity. For the prediction of the biodegradability the results obtained with the SAR-system are rather poor and have to be improved. Meanwhile the SAR-system is commercially available and can be ordered at the Fraunhofer Institute for Environmental Chemistry and Ecotoxicology, Schmallenberg (Germany).     

Determination of tenuazonic acid in human urine by means of a stable isotope dilution assay

The content of tenuazonic acid in human urine was determined by a stable isotope dilution assay (SIDA) that was recently developed for the analysis of food commodities and extensively re-validated for urine matrix in this study. Linearity of the response curve was proven between molar ratios n(labeled standard)/n(analyte) of 0.02–100. The limits of detection and determination were 0.2 and 0.6 μg/L, respectively. The mean recovery of the stable isotope dilution assay was 102?±?3 % in the range between 1.0 and 100 μg/L. Interassay precision was 6.7 % (relative standard deviation of three triplicate analyses of a human urine sample during 3 weeks). The method was applied to two studies dealing with urinary excretion of tenuazonic acid: In the first study, tenuazonic acid was quantified in the 24-h urine of six volunteers from Germany (three female, three male) in a concentration range of 1.3–17.3 μg/L or 2.3–10.3 ng/mg^?1 creatinine, respectively. In the second study, two volunteers (one female, one male) ingested 30 μg tenuazonic acid by consumption of naturally contaminated whole meal sorghum infant cereals and tomato juice, respectively. The urinary excretion of the ingested tenuazonic acid was 54–81 % after 6 h, depending on matrix and volunteer. After 24 h, 87–93 % of the ingested amount of tenuazonic acid was excreted, but the fate of the remaining about 10 % is open. Thus, it is not possible to exclude potential health hazards for the consumer, completely.

Direct Pyridazine Ring Synthesis from β-Cyano Esters. A Facile Synthesis of the Derivatives of Tetrahydro-3,6-pyridazinedione 3-Hydrazone

4-Substituted tetrahydro-3,6-pyridazinedione 3-hydrazones (2) (or their 3-hydrazino tautomers 3), useful intermediates in the synthesis of bicyclic pyridazine derivatives, were prepared in satisfactory yields in the reaction of the corresponding alkyl 3-substituted 3-cyanopropionates with hydrazine hydrate.     

pH‐Dependent Coordination of AgI Ions by Histidine: Experiment,Theory, and a Model for SilE

Artificial implants and biomaterials lack the natural defense system of our body and, thus, have to be protected from bacterial adhesion and biofilm formation. In addition to the increasing number of implanted objects, the resistance of bacteria is also an important problem. Silver ions are well‐known for their antimicrobial properties, yet not a lot is known about their mode of action. Silver is expected to interact on many levels, thus the development of silver resistance is very difficult. Nevertheless, some bacteria are able to resist silver, even at higher concentrations. One such defense mechanism of bacteria against heavy‐metal intoxication includes an efflux system. SilE, a periplasmic silver‐binding protein that is involved in this defense mechanism, has been shown to possess numerous histidine functions, which strongly bind to silver atoms, as demonstrated by ourselves previously. Herein, we address the question of how histidine binds to silver ions as a function of pH value. This property is important because the local proton concentration in cells varies. Thus, we solved the crystal structures of histidine–silver complexes at different pH values and also investigated the influence of the amino‐acid configuration. These results were completed by DFT calculations on the binding strength and packing effects and led to the development of a model for the mode of action of SilE.     

Base‐Stabilized Boryl and Cationic Haloborylene Complexes of Iron

The synthesis of base‐stabilized boryl and borylene complexes is reported. An N‐heterocyclic carbene (NHC)‐stabilized iron–dihydroboryl complex was prepared by two different routes including methane liberation and salt elimination. A range of base‐stabilized iron–dichloroboryl complexes was prepared by addition of Lewis bases to boryl complexes. Base‐stabilized, cationic monochloroborylene complexes were synthesized from these boryl complexes by halide abstraction by using weakly coordinating anions.     

Aldehyde‐Assisted Ruthenium(II)‐Catalyzed C?H Oxygenations

Versatile ruthenium(II) complexes allow for site‐selective C H oxygenations with weakly‐coordinating aldehydes. The challenging C H functionalizations proceed with high chemoselectivity by rate‐determining C H metalation. The new method features an ample substrate scope, which sets the stage for the step‐economical preparation of various bioactive heterocycles.     

Conductor‐like screening model for relaxed excited states: Implementation in the semiempirical method MSINDO

Two approaches to treat solvent polarization and reorientation effects for excited states of molecules and surfaces have been implemented in the recently developed MSINDO‐sCIS method (Gadaczek, Krause, Hintze, Bredow, J. Chem. Theory Comput. 2011, 7, 3675). They allow for an efficient calculation of analytical energy gradients and hence open the opportunity to investigate fluorescence effects or photochemical reactions in solution for large molecules that are difficult to treat with high‐level methods. Both approaches are based on the conductor‐like screening model (COSMO) (Klamt and Schüürmann, J. Chem. Soc., Perkin Trans. 1993, 2, 799) in combination with the configuration interaction singles (CIS) method (Foresman, Head‐Gordon, Pople, and Frisch, J. Phys. Chem. 1992, 96, 135). The paper gives a brief outline of the theoretical background. As a first application, solvent shifts of three well‐studied, environment‐sensitive fluorescent dyes (Kucherak, Didier, Mély, and Klymchenko, J. Phys. Chem. Lett. 2010, 1, 616) have been calculated and compared with experimental results and standard time‐dependent density functional theory. A statistical evaluation of MSINDO‐COSMO‐sCIS is provided for a set of 39 molecules suggested recently by Jacquemin et al. (Jacquemin, Planchat, Adamo, and Mennucci, J. Chem. Theory Comput. 2012, 8, 2359). Calculated vertical and adiabatic excitation energies and fluorescence energies are compared to experimental data. © 2014 Wiley Periodicals, Inc.     

A Rapid,Highly Sensitive and Selective Phosgene Sensor Based on 5,6-Pinenepyridine

The toxicity of phosgene (COCl₂) combined with its extensive use as a reactant and building block in the chemical industry make its fast and accurate detection a prerequisite. We have developed a carboxylic derivative of 5,6-pinenepyridine which is able to act as colorimetric and fluorimetric sensor for phosgene in air and solution. For the first time, the formation of a pyrido-[2,1-a]isoindolone was used for this purpose. In solution, the sensing reaction is extremely fast (under 5 s), selective and highly sensitive, with a limit of detection (LOD) of 9.7 nM/0.8 ppb. When fixed on a solid support, the sensor is able to detect the presence of gaseous phosgene down to concentrations of 0.1 ppm, one of the lowest values reported to date.     

Enantioselective Synthesis of Acyclic Orthogonally Functionalized Compounds Bearing a Quaternary Stereocenter Using Chiral Ammonium Salt Catalysis

We herein report an asymmetric protocol to access a series of orthogonally functionalized acyclic chiral target molecules containing a quaternary stereogenic center by carrying out the enantioselective α-alkylation of novel orthogonally functionalized dioxolane-containing cyanoacetates under chiral ammonium salt catalysis. By using just 1 mol % of Maruoka's spirocyclic ammonium salt catalysts enantioselectivities up to e.r.=97.5 : 2.5 could be achieved and further functional group manipulations of the products were carried out as well.