Use of the tubulin bound paclitaxel conformation for structure-based rational drug design

A new computational docking protocol has been developed and used in combination with conformational information inferred from REDOR-NMR experiments on microtubule bound 2-(p-fluorobenzoyl)paclitaxel to delineate a unique tubulin binding structure of paclitaxel. A conformationally constrained macrocyclic taxoid bearing a linker between the C-14 and C-3'N positions has been designed and synthesized to enforce this "REDOR-taxol" conformation. The novel taxoid SB-T-2053 inhibits the growth of MCF-7 and LCC-6 human breast cancer cells (wild-type and drug resistant) on the same order of magnitude as paclitaxel. Moreover, SB-T-2053 induces in vitro tubulin polymerization at least as well as paclitaxel, which directly validates our drug design process. These results open a new avenue for drug design of next generation taxoids and other microtubule-stabilizing agents based on the refined structural information of drug-tubulin complexes, in accordance with typical enzyme-inhibitor medicinal chemistry precepts.     

Adaptation of Cu/ZnO/Al_2O_3 to Temperature Change in Methanol Synthesis from CO_2 Hydrogenation

The induction behavior in CO2 hydrogenation was studied by varying the reaction temperature to investigate the adaptation of the Cu/ZnO/Al2O3 catalyst to the temperature change. The results indicated that a used catalyst had a tendency to keep the last running state in new reaction conditions for MeOH formation, and that this tendency was related to the difference in Cu/Cun+ ratio caused by CO2 and CO produced at different reaction temperatures. However, the reverse water-gas shift reaction (RWGS) induced at four temperatures was completely different from that of methanol synthesis. It implied that the two so-called competitive reactions in CO2+H2, RWGS and methanol synthesis, have different active centers.     

Ab initio investigations of the bound rovibrational levels of NeH 2 + , NeHD+, and NeD 2 +

Summary Bound rovibrational levels have been calculated for NeH ₂ ⁺ , NeHD⁺, and NeD ₂ ⁺ using three recent fits to an accurateab initio PES. The NeH ₂ ⁺ molecule behaves essentially as a linear molecule, the predicted rotational constant is 2.57 cm^–1. The fundamental frequencies are 811, 1189, and 1748 cm^–1 for the Ne-H ₂ ⁺ stretch, the Ne-H ₂ ⁺ bend and H ₂ ⁺ stretching modes, respectively.Dedicated to the 60th birthday of Prof. W. Kutzelnigg, Bochum     

Microfluidic devices for energy conversion: planar integration and performance of a passive, fully immersed H2-O2 fuel cell

We describe the fabrication and performance of a passive, microfluidics-based H2-O2 microfluidic fuel cell using thin film Pt electrodes embedded in a poly(dimethylsiloxane) (PDMS) device. The electrode array is fully immersed in a liquid electrolyte confined inside the microchannel network, which serves also as a thin gas-permeable membrane through which the reactants are fed to the electrodes. The cell operates at room temperature with a maximum power density of around 700 microW/cm(2), while its performance, as recorded by monitoring the corresponding polarization curves and the power density plots, is affected by the pH of the electrolyte, its concentration, the surface area of the Pt electrodes, and the thickness of the PDMS membrane. The best results were obtained in basic solutions using electrochemically roughened Pt electrodes, the roughness factor, R(f), of which was around 90 relative to a smooth Pt film. In addition, the operating lifetime of the fuel cell was found to be longer for the one using higher surface area electrodes.     

THE PHOTOSENSITIZERS BENZOPHENOXAZINE and THIAZINES: COMPREHENSIVE INVESTIGATION OF PHOTOPHYSICAL and PHOTOCHEMICAL PROPERTIES

Eight differently substituted title dye compounds have been investigated regarding intersystem crossing, triplet state, fluorescence and singlet excited state pKa properties. In general, non-halogenated oxazines and thiazines as well as a mono bromooxazine show very low triplet quantum yields, phi tau (less than 0.03) and relatively long triplet lifetimes (approximately 40 microseconds) in acidic methanol. The phi tau data correlate well with known singlet oxygen yields. In basic methanol no triplet transient is observed but a significant yield of a ground state transient protonated (base dye) form is produced with a short lifetime, approximately 400 ns. Fluorescence can be seen simultaneously from both the excited base and the protonated base dye forms in basic methanol. For iodinated oxazine or thiazines, the triplet yield increases and can be as high as 0.5 (diiodo case) in acidic methanol. The triplet lifetimes are further shortened to approximately 10 microseconds compared to the non-iodinated derivatives above. The triplet yields of the iodo compounds are higher or equal to known singlet oxygen yields. In basic methanol triplet yields up to 0.2 can be seen, the triplet lifetime are shortened still further to 1 microsecond but no observable protonated form is produced (in distinction to the non-iodinated cases). Consideration is given to the correlation of triplet and singlet oxygen yields, ground and excited pKa properties, spin-orbit coupling and internal conversion properties, solvent effects, and phototherapeutic activity of these dyes.     

TRYPTOPHAN FLUORESCENCE LIFETIMES AS A FUNCTION OF EXCITATION WAVELENGTH*

Abstract— –Fluorescence decay times of aqueous dilute solutions (?20 µM) of L-tryptophan have been determined using the phase shift technique as well as single photon-counting coupled with synchrotron radiation (ACO at Orsay and SPEAR at Stanford). Decay times were obtained as a function of the excitation wavelength (in the spectral region 220–320 nm) monitoring emission of λ> 320 nm (in certain specified cases, λ> 360 nm). We have found that, at neutral pH and 20°C. fluorescence decays are single exponentials and independent of the excitation wavelength; under these conditions we find τ= 3.1 ± 0.1 ns.     

A note on residually small varieties of semigroups

It is proved for any varietyG of groups that if the subdirectly irreducible groups inG form a set, and if the subdirectly irreducible representation algebras of groups inG form a set, then every finite group inG is Abelian. The result is essential for the characterization of residually finite varieties of semigroups.     

Stereoselective syntheses of highly functionalized bicyclo[3.1.0]hexanes: a general methodology for the synthesis of potent and selective mGluR2/3 agonists

[Chemical reaction: See text] A Et3Al mediated intramolecular epoxide opening, cyclopropanation reaction is described. The transformation provided highly functionalized bicyclo[3.1.0]hexane systems in high efficiency and with perfect H or F endo selectivity. Application of this reaction to the synthesis of mGluR2/3 agonist 1 (43% overall yield) and a few intermediates suitable for the synthesis of other bicyclo[3.1.0]hexane mGluR2/3 agonists is discussed.     

A PRELIMINARY INVESTIGATION OF THE USE OF LIMONENE FOR DETECTING SINGLET OXYGEN AS A COMPONENT OF POLLUTED AIR

Abstract— Exploratory experiments using simulated conditions indicate that the terpene, (+)-limonene can serve to detect O₂(¹Δ_g) in polluted atmospheres. ¹O₂ attack on limonene results in the formation of specific oxidation products in a specific distribution; quantitative identification of these products is a highly specific test for ¹O₂.