Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy

Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.     

Five Novel Taccalonolides from the Roots of the Vietnamese Plant Tacca paxiana

Chemical investigation of the roots of the Vietnamese plant Tacca paxiana resulted in the isolation of five new steroidal compounds, taccalonolide R ( 6 ), S ( 7 ), T ( 8 ), U ( 9 ), and V ( 10 ). Their structures were established on the basis of NMR and mass‐spectral data. In addition, the five known taccalonolides A ( 1 ), B ( 2 ), E ( 3 ), K ( 4 ), and N ( 5 ) were also isolated and identified.     

Expressive equivalence of least and inflationary fixed-point logic

We study the relationship between least and inflationary fixed-point logic. In 1986, Gurevich and Shelah proved that in the restriction to finite structures, the two logics have the same expressive power. On infinite structures however, the question whether there is a formula in IFP not equivalent to any LFP-formula was left open.

In this paper, we answer the question negatively, i.e. we show that the two logics are equally expressive on arbitrary structures. We give a syntactic translation of IFP-formulae to LFP-formulae such that the two formulae are equivalent on all structures.

As a consequence of the proof we establish a close correspondence between the LFP-alternation hierarchy and the IFP-nesting depth hierarchy. We also show that the alternation hierarchy for IFP collapses to the first level, i.e. the complement of any inflationary fixed point is itself an inflationary fixed point.     

Correlated polarization propagator calculations of static polarizabilities

We present a systematic comparison of the correlation contribution at the level of the second-order polarization propagator approximation (SOPPA ) and MP 2 to the static dipole polarizability of (1) Be, BeH^?, BH, CH⁺, MgH^?, AIH, SiH⁺, and GeH⁺; (2) BH₃, CH₄, NH₃, H₂O, HF, BF, and F₂; and (3) N₂, CO, CN^?, HCN, C₂H₂, and HCHO . Fairly extended basis sets were used in the calculations. We find that the agreement with experimental values is improved in SOPPA and MP .2 over the results at the SCF level. The signs and magnitudes of the correlation contribution in SOPPA are similar to those obtained in analytical derivative MP 2 calculations. However, it is not possible to say, in general, which method gives the largest correlation contribution or the best agreement with experiment, nor is it possible to make a priori prediction of the sign of the correlation contribution. For the first group of molecules, which have a quasi-degenerate ground state, additional CCDPPA and CCSDPPA calculations were performed and compared with polarizabilities obtained as analytical/numerical derivatives of the CCD and CCSD energies. The CCSDPPA results were found to be in better agreement with other calculations than were the SOPPA results, demonstrating the necessity of using methods based on infinite-order perturbation theory for these systems. © 1994 John Wiley & Sons, Inc.     

A mixed‐FEM formulation for nonlinear incompressible elasticity in the plane

This article deals with an expanded mixed finite element formulation, based on the Hu‐Washizu principle, for a nonlinear incompressible material in the plane. We follow our related previous works and introduce both the stress and the strain tensors as further unknowns, which yields a two‐fold saddle point operator equation as the corresponding variational formulation. A slight generalization of the classical Babu?ka‐Brezzi's theory is applied to prove unique solvability of the continuous and discrete formulations, and to derive the corresponding a priori error analysis. An extension of the well‐known PEERS space is used to define an stable associated Galerkin scheme. Finally, we provide an a posteriori error analysis based on the classical Bank‐Weiser approach. © 2002 John Wiley & Sons, Inc. Numer Methods Partial Differential Eq 18: 105–128, 2002     

Diffusive motion of iron microcrystals studied by Mössbauer spectroscopy

A new model is presented which explains well the dramatic decrease of the Mössbauer line intensities with raising temperatures for freely dispersed iron microscrystals. In contrast to other theories which consider mainly vibration to be responsible we discuss here the decrease in terms of large amplitude diffusive rotational or translational jumps of the particles. Such diffusive jumps lead — in agreement with the observation — to a strong reduction of the Mössbauer-intensity without broadening the line width in a noticeable way. The typical potential well for a diffusing particle in an equilibrium position is derived quantitatively to be 13 meV. The model might be important also for a new understanding of the dynamics of catalytic clusters either in contact with each other or with larger solid surfaces.Part of this work was supported by the DFG Sonderforschungsbereich 306, Konstanz     

Characteristics of Nd：GdVO4 Laser with Different Nd-Doping Concentrations

We report the properties of a compact diode-pumped continuous-wave Nd：GdV04 laser with a linear cavity and different Nd-doped laser crystals. In a 0.2at.% Nd-doped Nd：GdVO4 laser, 1.54 W output laser power is achieved at 912nm wavelength with a slope efficiency of 24.8% at an absorbed pump power of 9.4W. With 0.3at.% Nd-doping concentration, we can obtain the either single-wavelength emission at 1064nm or 912nm or the dual-wavelength emission at 1064nm and 912nm by controlling the incident pump power. From an incident pump power of 11.6 W, the 1064nm emission between ^4Fa/2 and ^4I11/2 is suppressed completely by the 912nm emission between ^4Fa/2 and ^4I9/2. We obtain 670 mW output of the 912nm single-wavelength laser emission with a slope efficiency of 5.5% by taking an incident pump power of 18.4 W. Using a Nd：GdV04 laser with 0.4at.% Nd-doping concentration, we obtain either the single-wavelength emission at 1064nm or the dual-wavelength emission at both 1064nm and 912nm by increasing the incident pump power. We observe a strong competition process in the dualavelength laser.