Roland Krämer

Fluorescent Chemosensors for Cu2+ Ions: Fast, Selective, and Highly Sensitive

Low cross-sensitivity for other metal ions and the ability to detect nanomolar concentrations of Cu2+ ions are the exciting properties of fluorescence sensors in which a fluorophore and a chelating group are discrete subunits of the same molecule. The spatial separation offers considerable flexibility in design, which is a prerequisite for the optimization of sensor properties. The activity of the “chemodosimeter” 1 of Czarnik et al. is based on the Cu2+-induced hydrolysis of the hydrazide group and the formation of fluorescent rhodamine B.

Determination of dabigatran in human plasma samples.

The oral direct thrombin inhibitor dabigatran effectively prevents arterial and venous thromboembolism using fixed doses without the need for adjustment according to laboratory results. Dabigatran is eliminated from the circulation by ∼80% through the kidneys. However, the in vitro anticoagulant effect of dabigatran may be necessary to determine in special patient populations such as in the elderly, for renal impairment, before operations, bleeding or thrombotic episodes, and to monitor self-compliance. Several clotting and thrombin-specific chromogenic substrate assays are available to analyze the biological activity of dabigatran. All of them are prolonged in the presence of dabigatran. This article reports the effects of dabigatran on clinical routine assays and the potential usefulness for determination in special risk groups of patients when overdose or lack of compliance are suspected.

Coronene-Containing N-Heteroarenes: 13 Rings in a Row

We describe the modular synthesis of three novel large N-heteroarenes, containing 9, 11, and 13 annulated rings. This modular system features fused azaacene units to a coronene nucleus. We evaluate the optical and electronic properties and the solid-state packing of the targets. The electronic properties of the 13-ring N-heteroarene allow the fabrication of a proof-of-concept thin-film transistor. Electron mobilities up to 8 × 10(-4) cm/(V s) were obtained for polycrystalline films.

Determination of rivaroxaban in human plasma samples.

Rivaroxaban is one of the novel oral direct factor Xa inhibitors, which is effective in preventing thromboembolic complications at fixed doses (i.e., once daily), without the need for dose adjustment according to laboratory monitoring. Nearly 60% of rivaroxaban is cleared from circulation by glomerular filtration, 30% of which is excreted as active drug. Therefore, as renal elimination plays a pivotal role in the metabolism of this drug, impairment of renal function may be important during anticoagulation with rivaroxaban over long periods of time. The assessment of the anticoagulant effect/concentration of rivaroxaban may thus be useful in special patient populations such as in the elderly and eldest, during acute diseases with concurrent dehydration, before surgery, during bleeding or thrombotic episodes, or to verify adherence to therapy. Rivaroxaban prolongs prothrombin time in a dose-dependent, linear fashion. Activated partial thromboplastin time (APTT) is also prolonged, but in an exponential manner. Substantial differences in test results might be generated by different thromboplastin and APTT reagents. One-step prothrombin-induced clotting time assay is sensitive to low concentrations of rivaroxaban. Chromogenic substrate assays specific for factor Xa are also sensitive to rivaroxaban. Several initiatives are currently ongoing to standardize the various methods to determine rivaroxaban in human plasma samples, some of which will be summarized in this article along with the dose-dependent effects of rivaroxaban on relevant coagulation parameters. Therefore, although rivaroxaban prolongs all coagulation assays used to assess the anticoagulant effects of most anticoagulants, the most specific assay cannot be identified at present. Moreover, clinical trials are needed to determine the relationship of assay results with bleeding or thrombotic complications.

Report of the Subcommittee of Control of Anticoagulation on the determination of the anticoagulant effects of rivaroxaban

To cite this article: Harenberg J, Marx S, Weiss C, Krämer R, Samama M, Schulman S, on behalf of the working party: methods to determine rivaroxaban of the Subcommittee on Control of Anticoagulation of the ISTH. Report of the Subcommittee of Control of Anticoagulation on the determination of the anticoagulant effects of rivaroxaban. J Thromb Haemost 2012; 10: 1433–6.

Rapid Phosphodiester Hydrolysis by Zirconium(IV)

A 3×109-fold faster cleavage of DNA dinucleotide 1 to thymidine and phosphate can be achieved under mild conditions (pH 5.5, 20°C) with a zirconium(IV) complex containing tris(hydroxymethyl)aminomethane as ligand [Eq. (1)]. In view of applications of artificial DNAses to molecular biology and gene therapy, non-redox-active zirconium(IV) is an alternative to the highly efficient but reduction-sensitive cerium(IV).

Far-Field Nanoscopy with Reversible Chemical Reactions**

These methods separate overlapping point-spread functions of nearby objects in time by light-inducedswitching of the fluorescent probe between a bright (“on”)and a dark (“off”) state.This principle is used in a spatially defined manner inSTED microscopy to decrease the size of the point-spreadfunction by a donut-shaped depletion pulse.

Electrospray mass spectrometry of the self-assembly of a capped polymetallic complex

Electrospray mass spectrometry gives direct insight into the metal complexes present in solutions of ligands L1, L2and Cul ions and into the self-assembly of the capped complex1; the results agree with UV–VIS spectrophotometric titration data.

DNA-templated catalysis using a metal-cleavable linker.

Catalytic release of carboxylates from their 8-hydroxyquinoline esters by Cu(II) complexes, both attached to peptide nucleic acid strands, is triggered by complementary DNA.

Evaluating the Conformational Role of an Allosteric CuII Ion in Anion Recognition and Catalysis by a Tricopper Complex

Structural and anion binding studies have provided an insight into the conformational role of an allosteric CuII ion in the trinuclear catalyst (L 2–2H). L 2 is a novel trinucleating ligand with pyridyl, pyrimidyl and amide donor groups. (L 2–2H)Cu (1) has been characterized by X-ray crystallography. The Cu ion is located at the allosteric site and coordinated by two amide N and two pyrimidine N atoms, the CuN4 plane is tetrahedrally distorted, and the complex adopts a helically twisted conformation. In contrast, the (L 2–2H)Cu3(μ4-C2O4) subunit of the dodecanuclear complex [(L 2–2H)4Cu12(μ4-C2O4)2(μ-OH)4(μ-Cl)4Cl4(H2O)2] (5) is roof-shaped, and the allosteric Cu is located on the top of a square-based pyramid. The oxalate coligand is coordinated by the two catalytic Cu ions in an unusual 1,4-μ-O,O bridging mode with an O ⃛O “bite length” of 2.6 Å and a Cu ⃛Cu distance of 6.4 Å. Intramolecular transesterification of the phosphodiester 2-(hydroxypropyl)-p-nitrophenyl phosphate (HPNP) by [(L 2–2H)Cu3]4+ was investigated, in comparison with the closely related complex [(L 3–2H)Cu3]4+ in which the ligand framework is somewhat less flexible. From a kinetic analysis of cleavage rate at varying HPNP concentrations, K HPNP (the equilibrium constant for binding of HPNP to the complex) and k cat (first-order rate constant for cleavage of HPNP when bound to the complex) parameters were derived: K HPNP=190 M-1 ([(L 2–2H)Cu3]4+) and 305 M-1 ([(L 3–2H)Cu3]4+), k cat=10×10-3 s-1 ([(L 2–2H)Cu3]4+) and 3.3×10-3 s-1 ([(L 3–2H)Cu3]4+). Anion binding constants of the complexes were determined by monitoring competitive inhibition of HPNP cleavage. The complexes have a high affinity to , , and , which appear to be of the appropriate size for bridging coordination, while “smaller” anions and are bound less efficiently. [(L 3–2H)Cu3]4+ has a higher affinity than [(L 2–2H)Cu3]4+ to HPNP but a lower affinity to the rather large anion . This is interpreted as a consequence of the reduced flexibility of [(L 3–2H)Cu3]4+, which slightly disfavours widening of the Cu ⃛Cu distance for incorporation of perrhenate. Similarly, the somewhat lower reactivity of [(L 3–2H)Cu3]4+ is attributed to the larger energy gap between the ground state and sterically more demanding (and less efficiently stabilized) transition state. Synthesis of L 2. Intramolecular cleavage of the phosphodiester 2-(hydroxypropyl)-p-nitrophenyl phosphate (HPNP). Proposed mechanism of HPNP cleavage by [(L n –2H)Cu3]4+, including estimated O ⃛O distances of bridging HPNP in the ground and transition state.