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1.
ACS Nano ; 7(5): 4030-41, 2013 May 28.
Article in English | MEDLINE | ID: mdl-23544750

ABSTRACT

Directed self-assembly processes of polymeric systems represent a powerful approach for the generation of structural hierarchy in analogy to biological systems. Herein, we utilize triiodide as a strongly polarizable counterion to induce hierarchical self-assembly of an ABC miktoarm star terpolymer comprising a polybutadiene (PB), a poly(tert-butyl methacrylate) (PtBMA), and a poly(N-methyl-2-vinylpyridinium) (P2VPq) segment. Hereby, the miktoarm architecture in conjunction with an increasing ratio of triiodide versus iodide counterions allows for a stepwise assembly of spherical micelles as initial building blocks into cylindrical structures and superstructures thereof. Finally, micrometer-sized multicompartment particles with a periodic lamellar fine structure are observed, for which we introduce the term "woodlouse". The counterion-mediated decrease in hydrophilicity of the corona-forming P2VPq block is the underlying trigger to induce this hierarchical structure formation. All individual steps and the corresponding intermediates toward these well-defined superstructures were intensively studied by scattering and electron microscopic techniques, including transmission electron microtomography.


Subject(s)
Molecular Conformation , Polymers/chemistry , Iodides/chemistry , Micelles , Models, Molecular , Polymers/chemical synthesis
2.
Langmuir ; 29(5): 1388-94, 2013 Feb 05.
Article in English | MEDLINE | ID: mdl-23311383

ABSTRACT

We investigate the self-assembly behavior of Janus particles with different geometries at a liquid-liquid interface. The Janus particles we focus on are characterized by a phase separation along their major axis into two hemicylinders of different wettability. We present a combination of experimental and simulation data together with detailed studies elucidating the mechanisms governing the adsorption process of Janus spheres, Janus cylinders, and Janus discs. Using the pendant drop technique, we monitor the assembly kinetics following changes in the interfacial tension of nanoparticle adsorption. According to the evolution of the interfacial tension and simulation data, we will specify the characteristics of early to late stages of the Janus particle adsorption and discuss the effect of Janus particle shape and geometry. The adsorption is characterized by three adsorption stages which are based on the different assembly kinetics and different adsorption mechanisms depending on the particle shape.


Subject(s)
Toluene/chemistry , Water/chemistry , Adsorption , Nanoparticles/chemistry , Particle Size , Surface Properties , Wettability
3.
J Colloid Interface Sci ; 374(1): 45-53, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22364711

ABSTRACT

We present the preparation and the characterization of the solution behavior and functional properties of superparamagnetic and/or fluorescent, thermo-responsive inorganic/organic hybrid particles with an intermediate protective silica shell and a smart polymer corona. These well-defined multifunctional nanogels were prepared via two consecutive encapsulation processes of superparamagnetic Fe(2)O(3) nanoparticles (NPs) and/or fluorescent CdSe(ZnS) semiconductor nanocrystals with a silica layer and a crosslinked poly(N-isopropylacrylamide) (PNIPAAm) polymer shell. First, the different NPs were entrapped into a silica shell using a microemulsion process. Therein, the precise adjustment of the conditions allows to entrap either several particles or single ones and to tailor the thickness of the silica shell in the range of 20-60 nm. In a second step, a polymer coating, i.e. thermosensitive PNIPAAm, was attached onto the surface of the multifunctional core-shell particles via free radical precipitation polymerization, furnishing multifunctional core-shell-corona hybrid nanogels. Analyses of the functional properties, i.e. optical brightness and magnetic moments, along with transmission electron microscopy reveal near monodisperse hybrid nanoparticles that retain the intrinsic properties of the original nanocrystals. Additionally, we demonstrate the drastically increased chemical stability due to the barrier properties of the intermediate silica layer that protects and shields the inner functional nanocrystals and the responsive character of the smart PNIPAAm shell.

4.
Biomacromolecules ; 12(10): 3805-11, 2011 Oct 10.
Article in English | MEDLINE | ID: mdl-21875143

ABSTRACT

The synthesis of galactose-displaying core-shell nanospheres exhibiting both fluorescent and magnetic properties by grafting a glycocopolymer consisting of 6-O-methacryloylgalactopyranose (MAGal) and 4-(pyrenyl)butyl methacrylate (PyMA) onto magnetic silica particles via thiol-ene chemistry is reported. Magnetization measurements indicated that neither the encapsulation of the iron oxide particles into silica nor the grafting of the glycocopolymer chains had a significant influence on the superparamagnetic properties. This not only simplifies the purification of the particles but may facilitate the use of the particles in applications such as hyperthermia or magnetic resonance imaging (MRI). Furthermore, the hydrophilic glycopolymer shell provided solubility of the particles in aqueous medium and enabled the uptake of the particles into the cytoplasm and nucleus of lung cancer cells via carbohydrate-lectin recognition effects.


Subject(s)
Lung Neoplasms/metabolism , Magnetic Resonance Imaging/methods , Magnetics/methods , Molecular Imaging/methods , Nanoparticles/chemistry , Nanospheres/chemistry , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Nucleus/ultrastructure , Chromatography, Gel , Cytoplasm/metabolism , Endocytosis/physiology , Ferric Compounds/chemistry , Fluorescent Dyes/analysis , Galactose/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Lung Neoplasms/pathology , Methacrylates/chemistry , Microscopy, Electron, Transmission , Nanoparticles/analysis , Nanoparticles/ultrastructure , Nanospheres/analysis , Nanospheres/ultrastructure , Particle Size , Pyrenes/analysis , Pyrenes/chemistry , Silicon Dioxide/chemistry , Sulfhydryl Compounds/chemistry
5.
Langmuir ; 27(16): 9807-14, 2011 Aug 16.
Article in English | MEDLINE | ID: mdl-21755956

ABSTRACT

We describe the first study on the self-assembly behavior of Janus cylinders at liquid/liquid interfaces. The Janus cylinders are characterized by a phase separation along the major axis into two hemicylinders of different wettability. The pendant drop technique and microscopic imaging were used to characterize the adsorption behavior and self-assembly of Janus cylinders at perfluorinated oil/dioxane and perfluorinated oil/dimethyl sulfoxide interfaces. According to the evolution of the interfacial tension and a series of TEM images taken during the cylinder adsorption, we will specify the characteristics of early to late stages of the Janus cylinder adsorption at a liquid-liquid interface and discuss the effect of Janus cylinder length and their concentration. We also establish that the broken symmetry of the corona leads to significantly higher interfacial activity as compared to homogeneous core-shell cylinders. The adsorption is characterized by three different adsorption stages: first, free diffusion to the interface, followed by continuous adsorption of cylinders including ordering and domain formation and, finally, additional packing with a rearrangement of domains and formation of a loose multilayer system.


Subject(s)
Colloids/chemistry , Nanostructures/chemistry , Wettability
6.
J Med Chem ; 54(9): 3206-21, 2011 May 12.
Article in English | MEDLINE | ID: mdl-21486038

ABSTRACT

The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT(3A) and 5-HT(1A) receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic ß(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.


Subject(s)
Antidepressive Agents/chemical synthesis , Depressive Disorder, Major/drug therapy , Piperazines/chemical synthesis , Sulfides/chemical synthesis , Animals , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Cell Line , Drug Partial Agonism , Drug Stability , Hippocampus/drug effects , Hippocampus/metabolism , Humans , In Vitro Techniques , Microsomes, Liver/metabolism , Oocytes/drug effects , Oocytes/physiology , Piperazines/chemistry , Piperazines/pharmacology , Radioligand Assay , Rats , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Receptors, Serotonin/metabolism , Receptors, Serotonin, 5-HT1/metabolism , Receptors, Serotonin, 5-HT3/metabolism , Recombinant Proteins/agonists , Recombinant Proteins/antagonists & inhibitors , Serotonin/metabolism , Serotonin 5-HT1 Receptor Agonists/chemical synthesis , Serotonin 5-HT1 Receptor Agonists/chemistry , Serotonin 5-HT1 Receptor Agonists/pharmacology , Serotonin 5-HT3 Receptor Antagonists/chemical synthesis , Serotonin 5-HT3 Receptor Antagonists/chemistry , Serotonin 5-HT3 Receptor Antagonists/pharmacology , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity Relationship , Sulfides/chemistry , Sulfides/pharmacology , Vortioxetine , Xenopus
7.
Bioorg Med Chem Lett ; 21(5): 1498-501, 2011 Mar 01.
Article in English | MEDLINE | ID: mdl-21292483

ABSTRACT

The identification and structure-activity relationships of 2-aminomethyl-1-aryl cyclopropane carboxamides as novel NK(3) receptor antagonists are reported. The compound series was optimized to give analogues with low nanomolar binding to the NK(3) receptor and brain exposure, leading to activity in vivo in the senktide-induced hypoactivity model in gerbils.


Subject(s)
Amides , Carboxylic Acids , Cyclopropanes/chemical synthesis , Receptors, Neurokinin-3/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Disease Models, Animal , Gerbillinae , Molecular Structure , Peptides/chemical synthesis , Peptides/chemistry , Peptides/pharmacology , Structure-Activity Relationship
8.
Org Lett ; 11(1): 221-4, 2009 Jan 01.
Article in English | MEDLINE | ID: mdl-19035838

ABSTRACT

A Pd-catalyzed, one-pot, two-step synthesis of 2-amidoindoles from ynamides and o-iodoanilines is reported. A key highlight of this sequence is that after the Sonogashira reaction, intramolecular cyclization to the indole occurs spontaneously without activation of the alkyne.


Subject(s)
Alkynes/chemistry , Amides/chemistry , Indoles/chemical synthesis , Aniline Compounds/chemistry , Catalysis , Indoles/chemistry , Ligands , Molecular Structure , Palladium/chemistry , Stereoisomerism
9.
J Org Chem ; 73(23): 9447-50, 2008 Dec 05.
Article in English | MEDLINE | ID: mdl-18991381

ABSTRACT

The yields of ynamides using Hsung's second generation protocol depend substantially on the quality of K(3)PO(4). Samples of K(3)PO(4) from different suppliers were investigated by various techniques, revealing that the use of pure and anhydrous K(3)PO(4) provides higher ynamide yields in comparison to samples contaminated with hydrates (K(3)PO(4) x 1.5 H(2)O and K(3)PO(4) x 7 H(2)O). With high quality K(3)PO(4), a number of ynamides were synthesized in yields of 52-91%. In addition, we report that ynamides can undergo regioselective hydroamination with carbamates.


Subject(s)
Alkynes/chemistry , Amides/chemistry , Chemistry, Organic/methods , Phosphates/chemistry , Potassium Compounds/chemistry , Carbamates/chemistry , Catalysis , Copper/chemistry , Models, Chemical , Potassium/chemistry , Spectrophotometry, Infrared/methods , Thermogravimetry/methods , Time Factors
10.
J Comb Chem ; 9(2): 301-5, 2007.
Article in English | MEDLINE | ID: mdl-17348735

ABSTRACT

Mechanically robust tablets of nanoporous magnesium aluminometasilicate with high surface area and porosity can be loaded with a variety of organic and inorganic reagents and catalysts. The scope of this novel dosing methodology is demonstrated through the evaluation of 14 diverse organic reactions, including Mitsunobu, Suzuki, and bromination reactions.


Subject(s)
Aluminum Silicates/chemistry , Indicators and Reagents/chemistry , Magnesium/chemistry , Aluminum Compounds , Catalysis , Magnesium Compounds , Nanotechnology , Silicates
11.
J Org Chem ; 71(3): 1230-2, 2006 Feb 03.
Article in English | MEDLINE | ID: mdl-16438542

ABSTRACT

A multistep solid-phase organic synthesis with resin-bound bismuth linker is described. The flexibilities inherent in this system through novel chemoselective cross-coupling reactions, in conjunction with multidirectional and/or traceless cleavage methodologies, are exploited.


Subject(s)
Biphenyl Compounds/chemistry , Bismuth/chemistry , Boronic Acids/chemistry , Molecular Structure , Stereoisomerism
12.
J Comb Chem ; 6(6): 934-41, 2004.
Article in English | MEDLINE | ID: mdl-15530121

ABSTRACT

Novel nonsymmetrical N-bi- and N-terarylpiperazines were synthesized on solid phase via three consecutive palladium-catalyzed cross-coupling reactions in which C-N, C-B, and C-C bonds are formed consecutively.

13.
J Org Chem ; 69(20): 6890-3, 2004 Oct 01.
Article in English | MEDLINE | ID: mdl-15387617

ABSTRACT

A general synthesis of resin-bound triaryl bismuthanes and resin-bound triaryl bismuth diacetates starting from commercially available chloromethyl polystyrene is reported. For the first time resin-bound bismuth has been utilized as part of a multidirectional linker system for solid-phase organic synthesis and as a resin-bound arylation reagent.

14.
Bioorg Med Chem Lett ; 14(15): 4027-30, 2004 Aug 02.
Article in English | MEDLINE | ID: mdl-15225720

ABSTRACT

Elevation of glycine levels and activation of the NMDA receptor by inhibition of the glycine transporter 1 (GlyT-1) is a potential strategy for the treatment of schizophrenia. A novel series of GlyT-1 inhibitors have been identified containing the 2-arylsulfanyl-phenylpiperazine motif. The most prominent member of this series, (R)-4-[5-chloro-2-(4-methoxy-phenylsulfanyl)-phenyl]-2-methyl-piperazin-1-yl-acetic acid (31) is a potent glycine transporter-1 inhibitor (IC(50)=150 nM), which elevated glycine levels in rat ventral hippocampus as measured by microdialysis in vivo at doses of 1.2-4.6 mg/kg s.c.


Subject(s)
Amino Acid Transport Systems, Neutral/antagonists & inhibitors , Antipsychotic Agents/chemical synthesis , Piperazines/chemical synthesis , Piperazines/pharmacology , Acetates/chemical synthesis , Acetates/chemistry , Acetates/pharmacology , Animals , Antipsychotic Agents/therapeutic use , Glycine/metabolism , Glycine Plasma Membrane Transport Proteins , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Kinetics , Models, Molecular , Molecular Conformation , Molecular Structure , Piperazines/chemistry , Rats , Receptors, N-Methyl-D-Aspartate/drug effects , Schizophrenia/drug therapy , Structure-Activity Relationship
15.
J Comb Chem ; 5(6): 842-50, 2003.
Article in English | MEDLINE | ID: mdl-14606814

ABSTRACT

Pretreatment of polystyrene beads with a nonpolar organic solvent is the key for the generation of mechanically robust tablets consisting of neat functionalized polystyrene beads, both alone and in combination with solid reagents or catalysts. The novel dosing methodology provides accurately preweighed tablets in virtually any shape and size and with excellent disintegration properties, speeding up parallel solution and solid phase synthesis. The use of tablets is demonstrated in parallel Mitsunobu and acylation reactions.


Subject(s)
Polystyrenes/chemistry , Tablets/chemistry , Technology, Pharmaceutical/methods , Catalysis
16.
J Org Chem ; 67(15): 5257-68, 2002 Jul 26.
Article in English | MEDLINE | ID: mdl-12126414

ABSTRACT

Iron-assisted S(N)Ar reactions were performed for the first time on solid phase, and a library of 36 unsymmetrically substituted phenylpiperazines and phenyl-1,4-diazepanes was synthesized with this novel strategy. The scope of iron-assisted S(N)Ar reactions on solid phase was investigated, and reactions of representative nucleophiles from groups VI (O, S, and Se) and V (N and P) of the periodic table were examined. Decomplexation of resin-bound iron complexes was achieved with 1,10-phenanthroline under irradiation, thereby overcoming the notorious disadvantages of decomplexation observed in solution-phase chemistry.

17.
J Org Chem ; 63(21): 7418-7420, 1998 Oct 16.
Article in English | MEDLINE | ID: mdl-11672392

ABSTRACT

Resin-bound 1-hydroxyimidazole, obtained by alkylation of the sodium salt of 1-hydroxyimidazole with chloromethyl polystyrene, was lithiated at C-2 with n-butyllithium. Subsequent treatment with carbon, halogen, or sulfur electrophiles followed by detachment from the solid support by heating with trifluoracetic acid at 100 degrees C for 20 h gave 2-substituted 1-hydroxyimidazoles in 52-93% yields.

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