Modeling robust QSAR 3: SOM-4D-QSAR with iterative variable elimination IVE-PLS: application to steroid, azo dye, and benzoic acid series

In the current paper we present a receptor-independent 4D-QSAR method based on self-organizing mapping (SOM-4D-QSAR) and in particular focus on its pharmacophore mapping ability. We use a novel stochastic procedure to verify the predictive ability of the method for a large population of 4D-QSAR models generated. This systematic study was conducted on a series of benzoic acids, azo dyes, and steroids that bind aromatase. We show that the 4D-QSAR method coupled with IVE-PLS provides a very stable and predictive modeling technique. The method enables us to identify the molecular motifs contributing the most to the fiber-dye affinity and the aromatase enzyme binding activity of the steroid. However, the method appeared much less effective for the benzoic acid series, in which the efficacy was limited by electronic effects strictly correlated to a single conformer.     

Novel dibenzothiophene chromophores with peripheral barbituric acceptors

A series of novel chromophores based on central 2,8-disubstituted dibenzothiophene (DBT) or dibenzothiophene-S,S-dioxide (DBTO) has been designed and prepared. The interconnection of DBT(O) central scaffold with two peripheral barbituric acceptors via various π-spacer allowed significant property tuning of target chromophores. Four new final chromophores and six DBT(O)-intermediates have been successfully synthesized and fully characterized. Experimental and calculated data showed that the fundamental properties are affected by the chromophore A-π-D-π-A or A-π-A-π-A arrangement (DBT vs. DBTO) and the π-linker (ethenylene vs. ethynylene). Thorough structure-property relationships have been elucidated and discussed in detail.     

Erstes Beispiel einer H-Verschiebung in ‘Thiocarbonyl-aminiden’ (N-(Alkylidensulfonio)aminiden)

First Example of an H-Shift in ‘Thiocarbonyl Aminides’ (N-(Alkylidenesulfonio)aminides) Reaction of benzyl azide ( 15a ) with the sterically hindered C?S group of 4,4-dimethyl-1,3-thiazole-5(4H)-thiones 14 (Scheme 3) and 1,1,3,3-tetramethylindane-2-thione ( 17 , Scheme 4) at 80° leads to the corresponding imines in high yield, without formation of any by-product. In contrast, 15a and 2,2,4,4-tetramethyl-3-thioxocyclobutanone ( 7 ) under the same conditions yielded, in addition to imine 19 , products 20a and 21 (Scheme 5). For the formation of 20a , a reaction mechanism via [1,4]-H shift in the intermediate ‘thiocarbonyl aminides’ 23 is proposed (Scheme 6). Product 21 as well as the dithiazole derivative 22 , which is formed only in the reaction with 4-nitrobenzyl azide ( 15c ), are formal adducts of the dipole 23 . Whereas precedents are known for the formation of cycloadducts of type 22 , the pathway to 21 is not known. Two possible mechanisms of its formation are proposed in Schemes 8 and 9.     

Impact of Heteroatom Substitution on Dual-State Emissive Rigidified 2-(2’-hydroxyphenyl)benzazole Dyes: Towards Ultra-Bright ESIPT Fluorophores**

2-(2’-Hydroxyphenyl)benzazole (HBX) fluorophores are well-known excited-state intramolecular proton transfer (ESIPT) emitters largely studied for their synthetic versatility, photostability, strong solid-state fluorescence and ability to engineer dual emission, thus paving the way to applications as white emitters, ratiometric sensors, and cryptographic dyes. However, they are heavily quenched in solution, due to efficient non-radiative pathways taking place as a consequence of the proton transfer in the excited-state. In this contribution, the nature of the heteroring constitutive of these rigidified HBX dyes was modified and we demonstrate that this simple structural modification triggers major optical changes in terms of emission color, dual emission engineering, and importantly, fluorescent quantum yield. Investigation of the photophysical properties in solution and in the solid state of a series of ethynyl-TIPS extended HBX fluorophores, along with ab initio calculations demonstrate the very promising abilities of these dyes to act as bright dual-state emitters, in both solution (even in protic environments) and solid state.     

Inclusion of menadione with cyclodextrins studied by calorimetry and spectroscopic methods

Complex formation of menadione with α‐, hydroxypropyl α‐, β‐, hydroxypropyl‐β‐, methyl‐β‐ and hydroxypropyl‐γ cyclodextrins in aqueous solution at 298.15 K was studied by using isothermal titration calorimetry, ¹H NMR, and UV–vis spectrophotometry. The experimental data indicated the partial insertion of menadione into macrocyclic cavity upon formation of two alternative types of 1:1 inclusion complexes, whose thermodynamic parameters (K, Δ_cG⁰, Δ_cH⁰, and Δ_cS⁰) were calculated. The influence of host size on the complex formation process was analyzed. β‐Cyclodextrin and its hydroxypropylated and methylated derivatives were found more effective binders towards menadione than α‐ and γ‐cyclodextrins. Copyright © 2007 John Wiley & Sons, Ltd.     

Reliability based limit design of steel frames with limited residual strain energy capacity

The aim of this paper is to take into consideration the influence of the limited load carrying capacity of the connections on the plastic limit state of elasto-plastic steel (or composite) framed structures under multi-parameter stochastic loading and probabilistically given conditions. In addition to the plastic limit design to control the plastic behaviour of the structure, bound on the complementary strain energy of the residual forces is also applied. This bound has significant effect for the load parameter. If the design uncertainties (manufacturing, strength, geometrical) are expressed by the calculation of the complementary strain energy of the residual forces a reliability based extended limit design problem is formed. The formulations of the problems yield to nonlinear mathematical programming which are solved by the use of sequential quadratic algorithm. The bi-level optimization procedure governed by the reliability index calculation. (© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Temperature dependence of the linewidths of shallow impurity spectral lines

A pronounced broadening of shallow donor transition linewidths in GaAs and CdTe by a factor of 2-2·5 on raising the sample temperature from 4 K to 10 K is reported. At low temperatures such impurity lines are inhomogeneously broadened by the Stark effect due to random electric fields arising from the ionized impurities in the crystal. The experimental observation is analysed and explained in terms of the temperature dependent spatial correlation between ionized donors and acceptors in the crystal.     

Mass spectrometry of some methyl esters of N-4-pyrimidinylamino acids: Rearrangements of the ions occurring on electron-impact ionization

The electron-impact-induced mass fragmentations of methyl esters of N-(1H-2-oxo-4-pyrimidinyl)ainino acids are reported. The loss of a ·COOCH₃ radical and the elimination of a methanol molecule were observed and possible mechanisms of these processes are proposed. The loss of a ·COOH radical and elimination of water were established, which suggests the rearrangement of the investigated esters into isomeric N-4-pyrimidinylamino acids.     

Pictet-Spengler reaction of biogenic amines with (2R)-N-Glyoxyloylbornane-10,2-sultam. Enantioselective synthesis of (S)-(+)-N-methylcalycotomine

(2R)-N-Glyoxyloylbornane-10,2-sultam reacted with dopamine hydrochloride, forming the Pictet-Spengler condensation product, which was further converted into (S)-(+)-N)-methylcalycotomine of high enantiomeric purity. The same kind of reaction with tryptamine hydrochloride gave the condensation product with 100% d.e.