Theo Schotten

Acyclic N-(azacycloalkyl)bisindolylmaleimides: Isozyme selective inhibitors of PKCβ

The synthesis and structure-activity relationship (SAR) trends of a new class of N-(azacycloalkyl)bisindolylmaleimides 1, acyclic derivatives of staurosporine, is described. The representative compound for this series (1e) exhibits an IC(50) of 40-50 nM against the human PKCbeta(1) and PKCbeta(2) isozymes and selectively inhibits the PKCbeta isozymes in comparison to other PKC isozymes (alpha, gamma, delta, epsilon, lambda, and eta). The series is also kinase selective for PKC in comparison to other ATP-dependent kinases. A comparison of the PKC isozyme and kinase activity of the series is made to the kinase inhibitor staurosporine.

Ex Post Glycoconjugation of Phthalocyanines

For the first time, fully fledged phthalocyanines (Pcs) were ex post glycoconjugated, that is, via 1,3-dipolar cycloaddition reaction. This divergent approach gains rapid access to a broad range of highly diverse Pcs bearing chemically sensitive substituents. This will be a breakthrough in generating structure-activity relationships (SAR) for the development of novel bioactive molecules.

Polymer-assisted self-assembly of superparamagnetic iron oxide nanoparticles into well-defined clusters: controlling the collective magnetic properties.

The combination of superstructure-forming amphiphilic block copolymers and superparamagnetic iron oxide nanoparticles produces new nano/microcomposites with unique size-dependent properties. Herein, we demonstrate the controlled clustering of superparamagnetic iron oxide nanoparticles (SPIOs) ranging from discretely encapsulated SPIOs to giant clusters, containing hundreds or even more particles, using an amphiphilic polyisoprene-block-poly(ethylene glycol) diblock copolymer. Within these clusters, the SPIOs interact with each other and show new collective properties, neither obtainable with singly encapsulated nor with the bulk material. We observed cluster-size-dependent magnetic properties, influencing the blocking temperature, the magnetoviscosity of the liquid suspension, and the r2 relaxivity for magnetic iron oxide nanoparticles. The clustering methodology can be expanded also to other nanoparticle materials [CdSe/CdS/ZnS core/shell/shell quantum dots (QDs), CdSe/CdS quantum dots/quantum rods (QDQRs), gold nanoparticles, and mixtures thereof].

Amphiphilic, cross-linkable diblock copolymers for multifunctionalized nanoparticles as biological probes

Nanoparticles (NPs) play an increasingly important role in biological labeling and imaging applications. However, preserving their useful properties in an aqueous biological environment remains challenging, even more as NPs therein have to be long-time stable, biocompatible and nontoxic. For in vivo applications, size control is crucial in order to route excretion pathways, e.g. renal clearance vs. hepato-biliary accumulation. Equally necessary, cellular and tissue specific targeting demands suitable linker chemistry for surface functionalization with affinity molecules, like peptides, proteins, carbohydrates and nucleotides. Herein, we report a three stage encapsulation process for NPs comprised of (1) a partial ligand exchange by a multidentate polyolefinic amine ligand, PI-N3, (2) micellar encapsulation with a precisely tuned amphiphilic diblock PI-b-PEG copolymer, in which the PI chains intercalate to the PI-N3 prepolymer and (3) radical cross-linking of the adjacent alkenyl bonds. As a result, water-soluble NPs were obtained, which virtually maintained their primal physical properties and were exceptionally stable in biological media. PEG-terminal functionalization of the diblock PI-b-PEG copolymer with numerous functional groups was mostly straightforward by chain termination of the living anionic polymerization (LAP) with the respective reagents. More complex affinity ligands, e.g. carbohydrates or biotin, were introduced in a two-step process, prior to micellar encapsulation. Advantageously, this pre-assembly approach opens up rapid access to precisely tuned multifunctional NPs, just by using mixtures of diverse functional PI-b-PEG polymers in a combinatorial manner. All constructs showed no toxicity from 0.001 to 1 μM (particle concentration) in standard WST and LDH assays on A549 cells, as well as only marginal unspecific cellular uptake, even in serum-free medium.

A universal approach to ultrasmall magneto-fluorescent nanohybrids.

Seeded emulsion polymerization is a powerful universal method to produce ultrasmall multifunctional magnetic nanohybrids. In a two-step procedure, iron oxide nanocrystals were initially encapsulated in a polystyrene (PS) shell and subsequently used as beads for a controlled assembly of elongated quantum dots/quantum rods (QDQRs). The synthesis of a continuous PS shell allows the whole construct to be fixed and the composition of the nanohybrid to be tuned. The fluorescence of the QDQRs and magnetism of iron oxide were perfectly preserved, as confirmed by single-particle investigation, fluorescence decay measurements, and relaxometry. Bio-functionalization of the hybrids was straightforward, involving copolymerization of appropriate affinity ligands as shown by immunoblot analysis. Additionally, the universality of this method was shown by the embedment of a broad scale of NPs.

In Situ Functionalization and PEO Coating of Iron Oxide Nanocrystals Using Seeded Emulsion Polymerization

Herein we demonstrate that seeded emulsion polymerization is a powerful tool to produce multiply functionalized PEO coated iron oxide nanocrystals. Advantageously, by simple addition of functional surfactants, functional monomers, or functional polymerizable linkers-solely or in combinations thereof-during the seeded emulsion polymerization process, a broad range of in situ functionalized polymer-coated iron oxide nanocrystals were obtained. This was demonstrated by purposeful modulation of the zeta potential of encapsulated iron oxide nanocrystals and conjugation of a dyestuff. Successful functionalization was unequivocally proven by TXRF. Furthermore, the spatial position of the functional groups can be controlled by choosing the appropriate spacers. In conclusion, this methodology is highly amenable for combinatorial strategies and will spur rapid expedited synthesis and purposeful optimization of a broad scope of nanocrystals.

Spirocyclic nonpeptide glycoprotein IIb–IIIa antagonists. Part 3: synthesis and SAR of potent and specific 2,8-diazaspiro[4.5]decanes

The synthesis and biological activity of analogues containing spiro piperidinylpyridine and pyrrolidinylpyridine templates are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of the spiro structures as central template for nonpeptide RGD mimics.

Spirocyclic nonpeptide glycoprotein IIb-IIIa antagonists. Part 1: design of potent and specific 3,9-diazaspiro[5.5]undecanes.

The synthesis and biological activity of novel glycoprotein IIb-IIla antagonists containing the 3,9-diazaspiro[5.5]undecane nucleus are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of the spirocyclic structures as a central template for nonpeptide RGD mimics.

Fused bicyclic Gly-Asp β-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.

Highly stereoselective preparation of 3,3-disubstituted acrylates on polyethylene glycol

Abstract The highly stereoselective preparation of sterically hindered ( E ) and ( Z )-3,3-diaryl acrylic acid esters using a parallel synthesis approach is described. The liquid phase reaction utilises polyethylene glycol monomethyl ether 5000 (mPEG 5000) as a soluble polymeric support and phase-transfer agent.