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.     

Expected Reflection Distance in G(r, 1, n) after a Fixed Number of Reflections

Extending to r > 1 a formula of the authors, we compute the expected reflection distance of a product of t random reflections in the complex reflection group G(r, 1, n). The result relies on an explicit decomposition of the reflection distance function into irreducible G(r, 1, n)-characters and on the eigenvalues of certain adjacency matrices.Received December 8, 2003     

The Interaction of Shocks with Dispersive Waves II. Incompressible-Integrable Limit

This is the second in a two-part series of articles in which we analyze a system similar in structure to the well-known Zakharov equations from weak plasma turbulence theory, but with a nonlinear conservation equation allowing finite time shock formation. In this article we analyze the incompressible limit in which the shock speed is large compared to the underlying group velocity of the dispersive wave (a situation typically encountered in applications). After presenting some exact solutions of the full system, a multiscale perturbation method is used to resolve several basic wave interactions. The analysis breaks down into two categories: the nonlinear limit and the linear limit, corresponding to the form of the equations when the group velocity to shock speed ratio, denoted by ε, is zero. The former case is an integrable limit in which the model reduces to the cubic nonlinear Schrödinger equation governing the dispersive wave envelope. We focus on the interaction of a “fast” shock wave and a single hump soliton. In the latter case, the ε=0 problem reduces to the linear Schrödinger equation, and the focus is on a fast shock interacting with a dispersive wave whose amplitude is cusped and exponentially decaying. To motivate the time scales and structure of the shock-dispersive wave interactions at lowest orders, we first analyze a simpler system of ordinary differential equations structurally similar to the original system. Then we return to the fully coupled partial differential equations and develop a multiscale asymptotic method to derive the effective leading-order shock equations and the leading-order modulation equations governing the phase and amplitude of the dispersive wave envelope. The leading-order interaction equations admit a fairly complete analysis based on characteristic methods. Conditions are derived in which: (a) the shock passes through the soliton, (b) the shock is completely blocked by the soliton, or (c) the shock reverses direction. In the linear limit, a phenomenon is described in which the dispersive wave induces the formation of a second, transient shock front in the rapidly moving hyperbolic wave. In all cases, we can characterize the long-time dynamics of the shock. The influence of the shock on the dispersive wave is manifested, to leading order, in the generalized frequency of the dispersive wave: the fast-time part of the frequency is the shock wave itself. Hence, the frequency undergoes a sudden jump across the shock layer.In the last section, a sequence of numerical experiments depicting some of the interesting interactions predicted by the analysis is performed on the leading-order shock equations.     

From monomeric to polymeric ferroelectric liquid crystals A comparative study of ferroelectric properties

Two new ferroelectric oligosiloxanes, a cyclic tetramer and a twin, have been synthesized. By a comparative study with their corresponding monomer and side chain polysiloxanes, the influence of oligo- and polymerization on the liquid crystalline and ferroelectric properties have been investigated. Polymerization leads to a stabilization of LC phases through increase of the clearing temperatures and suppression of crystallization. Oligomerization also leads to mesophase broadening, but, due to the low degree of polymerization, the effect is inferior to the linear polysiloxanes. The low viscosity of the oligosiloxanes ensures response times in the microsecond region, thus being comparable with their monomer and conventional LMWFLCs. It is found that polymerization increases the spontaneous polarization P_s. This is attributed to the density increase after polymerization, enhancing the inter-mesogenic interactions. The collective and local dynamics of the OFLCs are influenced differently with respect to their molecular structures. Each oligomer is already a good model for its corresponding polymer concerning the soft mode dynamics. For the local β-relaxation a similar temperature dependence of the relaxation times τ for the cyclic tetramer and for the side chain polysiloxanes is observed. The long axial rotation of the twin, having a very efficient decoupling, is significantly faster, thus resembling the monomer.     

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     

Synthesis and applications of chiral bis-THF in asymmetric synthesis

The synthesis of enantiopure bis-THF is described, starting from d-mannitol. Bis-THF is used as chiral ligand for organolithium reagents in four different reactions. The enantioselectivity provided by this ligand is moderate, and the asymmetric induction is in line with the expected model.     

Elliott-Morse measures and Kakutani's dichotomy theorem

Dedicated to the memory of John Oxtoby