A novel strategy to synthesize amphiphilic surface-compartmentalized nanoparticles based on linear ABC triblock copolymers is presented. These so-called Janus micelles consist of a cross-linked core and a corona with a "northern" and a "southern" hemisphere. Selectively cross-linking spherical domains of the polybutadiene middle block in a well-ordered bulk morphology of a polystyrene-blockpolybutadiene-block-poly(methyl methacrylate) triblock copolymer (SBM) leads to the conservation of the compartmentalization of the outer blocks after dissolution of the material. Multi-angle laser light scattering gel permeation chromatography, fluorescence correlation spectroscopy, small-angle neutron scattering, and static and dynamic light scattering, as well as scanning force microscopy, indicate the existence of an equilibrium between molecularly dissolved Janus micelles (unimers) and aggregates (multimers), so-called supermicelles.

We describe the synthesis and the solution properties of Janus micelles containing a polybutadiene (PB) core and a compartmentalized corona consisting of a poly(methacrylic acid) (PMAA) and a polystyrene (PS) hemisphere. The Janus micelles were obtained via cross-linking the middle block of a microphase-separated PS-block-PB-block-PMMA triblock copolymer in the bulk state, followed by alkaline hydrolysis of the poly(methyl methacrylate) (PMMA) ester groups. Results of fluorescence correlation spectroscopy, field flow fractionation, light scattering, cryogenic transmission electron microscopy, scanning electron microscopy, and scanning force microscopy indicate that above a critical aggregation concentration of about 0.03 g/L spherical supermicelles are formed from about 30 PS-PMAA micelles in aqueous solution in the presence of NaCl. These supermicelles have radii of 40-60 nm, significantly increasing on ionization (pH >6). In addition, very large spherical objects are observed with radii of 100-250 nm.

Amphiphilic diblock copolymers, poly(n-butyl acrylate)-block-poly(acrylic acid) (PnBA-PAA), with narrow molecular weight distribution (PDI ≤ 1.07) were prepared by atom transfer radical polymerization (ATRP) of n-butyl acrylate and tert-butyl acrylate (tBA), followed by selective acidolysis of the PtBA block. These polymers possess a soft PnBA hydrophobic block with a constant chain length of 90−100 monomer units and pH- and ionic strength-sensitive hydrophilic PAA block with DPPAA = 33−300 AA monomer units. They were expected to form stimuli-responsive micelles. The block copolymers with DPPAA ≥ 100 are directly soluble in water at pH > 4.7. Pyrene steady-state fluorescence spectroscopy and fluorescence correlation spectroscopy (FCS) studies indicate the existence of a very low critical micelle concentration (cmc ∼ 10-8 mol/L). The number-average hydrodynamic radii of the micelles, as determined by FCS, range from 28 to 55 nm, depending on the PAA block length. FCS data indicate that micellar sizes significantly decrease upon dilution for salt-free systems. This is attributed to a dynamic, but kinetically controlled, behavior of these self-assembled nanostructures. In saline solutions the micellar sizes remain constant above the “apparent” cmc (cmc*), which is attributed to slower dynamics of unimer exchange between micelles.

We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties.

Bionanoparticles, such as the cowpea mosaic virus, can stabilize oil droplets in aqueous solutions by self‐assembly at liquid interfaces. Subsequent cross‐linking of the bionanoparticles transforms the assemblies into robust membranes that have covalent inter‐bionanoparticle connections. The resulting membranes are nanoscopically thin sheets (see SANS image (SANS=small‐angle neutron scattering)), which were examined by fluorescent labeling.

We investigate the microdomain orientation kinetics of concentrated block copolymer solutions exposed to a dc electric field by time-resolved synchrotron small-angle X-ray scattering. As a model system, we use a lamellar polystyrene-b-polyisoprene block copolymer dissolved in toluene. Our results indicate two different microscopic mechanisms, i.e., nucleation and growth of domains and grain rotation. The former dominates close to the order-disorder transition, while the latter prevails under more strongly segregated conditions. This conclusion is corroborated by computer simulations based on dynamic density functional theory. The orientation kinetics follows a single-exponential behavior with characteristic time constants varying from a few seconds to some minutes depending on polymer concentration, temperature, and electric field strength. From the experimental results we deduce optimum conditions for the preparation of highly anisotropic bulk polymer samples via solvent casting in the presence of an electric field.

We investigate the microscopic mechanisms responsible for microdomain alignment in block copolymer solutions exposed to an electric field. Using time-resolved synchrotron small-angle x-ray scattering, we reveal two distinct processes, i.e., grain boundary migration and rotation of entire grains, as the two dominant microscopic mechanisms. The former dominates in weakly segregating systems, while the latter is predominant in strongly segregated systems. The kinetics of the processes are followed as a function of polymer concentration and temperature and are correlated to the solution viscosity.

Dual inhibition of the prostaglandin (PG) and leukotriene (LT) biosynthetic pathway is supposed to be superior over single interference, both in terms of efficacy and side effects. Here, we present a novel class of dual microsomal PGE(2) synthase-1/5-lipoxygenase (5-LO) inhibitors based on the structure of pirinixic acid [PA, 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)acetic acid, compound 1]. Target-oriented structural modification of 1, particularly alpha substitution with extended n-alkyl or bulky aryl substituents and concomitant replacement of the 2,3-dimethylaniline by a biphenyl-4-yl-methane-amino residue, resulted in potent suppression of mPGES-1 and 5-LO activity, exemplified by 2-(4-(biphenyl-4-ylmethylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (7b, IC(50) = 1.3 and 1 microM, respectively). Select compounds also potently reduced PGE(2) and 5-LO product formation in intact cells. Importantly, inhibition of cyclooxygenases-1/2 was significantly less pronounced. Taken together, these pirinixic acid derivatives constitute a novel class of dual mPGES-1/5-LO inhibitors with a promising pharmacological profile and a potential for therapeutic use.