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.     

Dynamic instability of thin viscoelastic films under lateral stress

We study the influence of lateral stress on the stability of thin viscoelastic films. The free surface of a deposited film under stress is shown to undergo an instability initiated by an anisotropic diffusion of the polymer molecules. This instability ultimately results in the formation of holes provided that the initial surface fluctuations are larger than a critical value. The latter is found to decrease when increasing the stress. An increase of the holes number density with the stress is therefore predicted. Most interestingly, the holes number density is also predicted to increase when increasing the molecular weight of the polymers. Additionally, we demonstrate that the friction of the substrate suppresses any spatial coherence between holes on large length scales. These predictions explain recent experimental observations made on thin spin-coated polystyrene films [G. Reiter, Nat. Mater. 4, 754 (2005)10.1038/nmat1484].     

Highly dispersive large mode area photonic bandgap fiber

An all-silica photonic bandgap fiber composed of a low-index core surrounded by alternating high- and low-index rings allows us to achieve a large mode area (500 microm(2)) and large chromatic dispersion. Sharp resonances from the even Bragg mode to odd ring modes theoretically lead to 20,000 ps/(nm km) chromatic dispersion when large bends are applied. By nature, sharp resonances are sensitive to inhomogeneities along the fiber length. Under experimental conditions, the resonances are broadened and the dispersion coefficient is decreased to 1000 ps/(nm km). However, to the best of our knowledge, this is the largest dispersion coefficient reported using a large mode area fiber.     

Effective temperature in driven vortex lattices with random pinning

We study numerically correlation and response functions in nonequilibrium driven vortex lattices with random pinning. From a generalized fluctuation-dissipation relation, we calculate an effective transverse temperature in the fluid moving phase. We find that the effective temperature decreases with increasing driving force and becomes equal to the equilibrium melting temperature when the dynamic transverse freezing occurs. We also discuss how the effective temperature can be measured experimentally from a generalized Kubo formula.     

Scattering Below Critical Energy for the Radial 4D Yang-Mills Equation and for the 2D Corotational Wave Map System

Given g and f  =  gg′, we consider solutions to the following non linear wave equation :

Capillary-gravity waves generated by a slow moving object

We investigate theoretically and experimentally the capillary-gravity waves created by a small object moving steadily at the water-air interface along a circular trajectory. It is well established that, for straight uniform motion, no steady waves appear at velocities below the minimum phase velocity c(min)=23 cm s(-1). We demonstrate that no such velocity threshold exists for a steady circular motion, for which, even for small velocities, a finite wave drag is experienced by the object. This wave drag originates from the emission of a spiral-like wave pattern. Our results are in good agreement with direct experimental observations of the wave pattern created by a circularly moving needle in contact with water. Our study leads to new insights into the problem of animal locomotion at the water-air interface.     

Host-guest interaction between cyclen based macrotricyclic ligands and phosphate anions. A potentiometric investigation

The host-guest interaction between orthophosphate, pyrophosphate and triphosphate anions and three cyclen based macrotricyclic ligands possessing ortho- (TOC), meta- (TMC) and para-xylenyl (TPC) linkers was investigated by potentiometric measurements. The ternary species present in solution and their stability constants have been determined. The different behaviours are explained in terms of hydrogen bond formation and coulombic attraction between the organic host and the inorganic guest. The selectivity, illustrated with species distribution diagrams, is discussed. The results unambiguously showed the importance of the distance between the two cyclen cores and emphasized the increasing of the triphosphate species selectivity together with the cavity size of the ligand. A comparison of the present results with those obtained with their mono-bridged homologues is also discussed.     

Chemical biology of salinomycin

Cancer stem cells (CSC) have been shown to be refractory to conventional therapeutic agents, can promote metastasis, and have been linked to cancer relapse. The natural product Salinomycin has been identified by means of high throughput phenotypic screening as a selective killer of CSC in vitro and in vivo. In this article we comprehensively review the chemistry of Salinomycin, documenting early total syntheses, along with strategies that have been developed over the years to effectively modify this natural product at key positions with the view to establish a robust structure-activity-relationship and to delineate the complex mechanism of action of this fascinating molecule in the context of cancer research. Then, we document the biology of Salinomycin, putting forward phenotypic alterations that have been observed in the relevant biological models and highlighting how chemistry has been instrumental in discovering unprecedented physiological features of cancer stem cells that can be exploited for therapeutic benefits.     

Détermination de l'énergie de conjugaison des acides naphtoǐques

The present paper deals with the experimental and theoretical determination of energies of conjugation of organic molecules.A computation process has been applied, first to simple molecules comprising an hydrocarbon (styrene), an oxygen function (benzaldehyde) and a nitrogen function (aniline). The results are compared with those obtained from the literature.The application of this computation process to naphthoic acids permits the determination of energies of conjugation and isomerization of these molecules.     

A Global Existence Result for the Compressible Navier–Stokes Equations in the Critical L p Framework

The present paper is dedicated to the global well-posedness issue for the barotropic compressible Navier–Stokes system in the whole space mathbbR^d{mathbb{R}^d} with d ≧ 2. We aim at extending the work by Danchin (Inventiones Mathematicae 141(3):579–614, 2000) to a critical framework which is not related to the energy space. For small perturbations of a stable equilibrium state in the sense of suitable L ^p -type Besov norms, we establish the global existence. As a consequence, like for incompressible flows, one may exhibit a class of large highly oscillating initial velocity fields for which global existence and uniqueness holds true. In passing, we obtain new estimates for the linearized and the paralinearized systems which may be of interest for future works on compressible flows.