E-olefin dipeptide isostere incorporation into a polypeptide backbone enables hydrogen bond perturbation: probing the requirements for Alzheimer's amyloidogenesis

Herein, we report a stereospecific E-olefin dipeptide isostere synthesis that can be used to make gram quantities of the Phe-Phe isostere desired for eliminating a specific backbone H-bond donor and acceptor in the Alzheimer's disease related Abeta peptide. The Phe19-Phe20 E-olefin analogue of Abeta(1-40) was prepared by solid-phase peptide synthesis and was subjected to amyloidogenesis conditions. This analogue can aggregate into spherical morphologies but does not progress on to form protofibrils or fibrils as is the case for the all-amide sequence, providing insight into the structural requirements for amyloidogenesis.     

Photochemistry of condensed isoxazolines

Summary The condensed bridged isoxazolines4 are rearranged on irradiation with a low-pressure mercury lamp exclusively into condensed derivatives of tetrahydropyridine5. The selectivity of the rearrangement is due to a stabilization of the biradical8 by the overlap of the radical-electrons with -electrons of the C=C double bond and the heterocyclic ring. Quantum yields of the photorearrangement, established from the consumption of the starting materials4, were determined.

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Photochemie kondensierter Isoxazoline

Zusammenfassung Die kondensierten überbrückten Isoxazoline4 werden durch Bestrahlen mit einer Niederdruckquecksilberlampe ausschließlich zu kondensierten Tetrahydropyridinderivaten (5) umgelagert. Die Selektivität der Umlagerung beruht auf der Stabilisierung des Diradikals8 durch Überlappung der ungepaarten Elektronen mit -Elektronen der C=C-Doppelbindung und des Heterocyclus. Aus dem Verbrauch an Ausgangsmaterial (4) wurden Quantenausbeuten der Photoumlagerung bestimmt.

     

Implementation and use of the method of prudent ascent in conformational analysis using molecular mechanics

In two-dimensional conformational analysis the current practice is to perform an energy minimization for all possible combinations of two dihedral angles in the molecule, in a fixed order, and apply a certain dihedral angle step-size. A newly developed method is presented in which the order of the evaluation points on the energy-surface is not fixed, but is dependent on all previous results in a way which we call “the method of prudent ascent.” In this method the most promising calculation is carried out first, thus minimizing the risk of atomic collisions. In order to be able to take care of the many additional degrees of conformational freedom present in, e.g., carbohydrate molecules, all minimizations are performed using a set of different promising starting conformations on the basis of previous calculations, and only the lowest energy result for each point is saved. An application of the method to conformational analysis of methyl-cellobiose and the artificial sweetener trichlorogalactosucrose is also presented.     

State vectors and propagators in many-electron theory. A unified approach

A unitary group formulation of the many-electron problem is employed to give explicit representations of state vectors which are convenient for the discussion of progerties derived from propagatorcalculations. New results are obtained concerning the nature of various random-phase-like approximations and ground state representatives are generated from consistency requirements for the spectral resolution of the polarization propagator. The explicit solution admits the calculation of ground state average values for arbitrary operators and a variational upper bound to the ground state energy.     

Determination of Low Contents of Fenpiverine Bromide by Extraction Spectrophotometry

An ion-pair extraction spectrophotometry method was developed for the determination of fenpiverine bromide in tablets. To determine this substance it was necessary to find experimental conditions that would allow eliminating the influence of other components of the tablets. Attention was paid to the fact that a suitable pH of water phase was necessary to achieve high selectivity.Received December 11, 2002; accepted April 24, 2003 Published online July 28, 2003     

Improving the efficiency and convergence of geometry optimization with the polarizable continuum model: new energy gradients and molecular surface tessellation

New equations are derived and implemented for efficient and accurate computation of solvation energy derivatives for the conductor-like polarizable continuum model (C-PCM) and the isotropic integral equation formalism polarizable continuum model (IEF-PCM). Two new molecular surface tessellation procedures GEPOL-RT and GEPOL-AS that generate near continuous potential energy surfaces are proposed for PCM geometry optimization. The combined use of these new techniques leads to efficient and convergent geometry optimizations with the PCMs.     

Splicing I: Using mixed basis sets in ab initio calculations

The effect of mixing (or “splicing”) extended and minimal basis sets on molecular properties such as geometries, Mulliken charges, dipoles, and internal rotation barriers was studied for several test molecules. The effect is gauged by comparison with full extended basis set calculations. It is found that splicing improves most properties relative to full minimal basis set calculations, and little accuracy is lost if the splicing is done in a judicious manner.     

Proton-ionizable crown compounds. 11. Synthesis of macrocyclic ligands containing two sulfonamide groups and chloro substituents or pyridine subcyclic units and a preliminary study of cation transport by three of these ligands

Five new macrocyclic ligands each containing two sulfonamide groups have been prepared. Three of these compounds contain one or two chloro substituents and the other two have one or two pyridine subcyclic units. A seventeen-membered ring ligand (4) was found to be an excellent transport agent for all alkali metal cations in a water-methylene chloride-water bulk liquid membrane system when the pH of the source phase was 13 or higher. The chlorine-substituted analog (5) was a poor transport agent for the alkali metal cations possibly because the chlorine atom blocked entry to the macrocycle cavity. An open-chain analog containing two sulfonamide groups was particularly effective in transporting cesium ions.     

AB initio SCF LCAO MO Calculations on styrene

Minimal basis set ab initio SCF LCAO MO calculations with gaussian-type have been performed for different conformations of the styrene molecule. The computations show the molecule to be planar and the rotational barrier of the vinyl group is estimated to 3.9 kcal/mole.