Ultrafast electronic relaxation pathways of the molecular photoswitch quadricyclane

The light-induced ultrafast switching between molecular isomers norbornadiene and quadricyclane can reversibly store and release a substantial amount of chemical energy. Prior work observed signatures of ultrafast molecular dynamics in both isomers upon ultraviolet excitation but could not follow the electronic relaxation all the way back to the ground state experimentally. Here we study the electronic relaxation of quadricyclane after exciting in the ultraviolet (201 nanometres) using time-resolved gas-phase extreme ultraviolet photoelectron spectroscopy combined with non-adiabatic molecular dynamics simulations. We identify two competing pathways by which electronically excited quadricyclane molecules relax to the electronic ground state. The fast pathway (<100 femtoseconds) is distinguished by effective coupling to valence electronic states, while the slow pathway involves initial motions across Rydberg states and takes several hundred femtoseconds. Both pathways facilitate interconversion between the two isomers, albeit on different timescales, and we predict that the branching ratio of norbornadiene/quadricyclane products immediately after returning to the electronic ground state is approximately 3:2

Catalytically Active Silica Nanoparticle-Based Supramolecular Architectures of Two Proteins - Cellobiose Dehydrogenase and Cytochrome c on Electrodes

Artificial nanobiomolecular architectures that follow natural examples in protein assembly become more and more important from basic and applied points of view. Our study describes the investigation on cellobiose dehydrogenase (CDH), cytochrome c (cyt c), and silica nanoparticles (SiNP's) for the construction of fully catalytically active supramolecular architectures on electrodes. We report on intraprotein, interprotein, and direct electron-transfer reaction cascades of cellobiose dehydrogenase and cytochrome c immobilized in multiple supramolecular layers. Carboxy-modified SiNP's are used to provide an artificial matrix, which enables protein arrangement in an electroactive form. Direct and interprotein electron transfer has been established for a two-protein system with CDH and cyt c in a layered architecture for the first time. We also highlight that the glycosylation of CDH and the silica nanoparticle size play key roles in the mode of operation in such a complex system. The response of the specific substrate, here lactose, can be tuned by the number of immobilized nanobiomolecular layers

A cassette-dosing approach for improvement of oral bioavailability of dual TACE/MMP inhibitors.

The structural features contributing to the different pharmacokinetic properties of the TACE/MMP inhibitors TNF484 and Trocade were analyzed using an in vivo cassette-dosing approach in rats. This enabled us to identify a new lead compound with excellent pharmacokinetic properties, but weaker activity on the biological targets. Directed structural modifications maintained oral bioavailability and restored biological activity, leading to a novel compound almost equipotent to TNF484 in vivo, but with a more than tenfold higher oral bioavailability

Electrocatalytically active multi-protein assemblies using nanoscaled building blocks

Biosensors based on nanomaterials constitute an emerging area of interdisciplinary research. In particular in electrochemical sensors, electron transfer cascades can be used for defined signal generation. Our study describes the investigation of silica nanoparticles (SiNPs), DNA, cytochrome c (cyt c) and cellobiose dehydrogenase (CDH) for the development of catalytically active multi-protein assemblies. We report on direct and interprotein electron transfer reaction cascades of CDH and cyt c in an immobilized form by means of nanoscaled building blocks: Carboxy-modified SiNPs, and DNA. The building blocks provide an artificial matrix, which permit protein arrangement in an electro- and catalytically-active form. Multilayered protein architectures on electrodes featuring direct and interprotein electron transfer by the use of entirely different nanoscaled building blocks has been established for the first time. In addition we highlight, that the secondary building blocks (DNA or SiNPs) used for the construction as well as the glycosylation of the enzyme (CDH) play a key role for the mode of operation in such complex entities

ICE-protease inhibitors block murine liver injury and apoptosis caused by CD95 or by TNF-alpha

The two apoptosis receptors of mammalian cells, i.e. the 55 kDa TNF receptor (TNF-R1) and CD95 (Fas/APO1) are activated independently of each other, however, their signaling involves a variety of ICE-related proteases. We used a cell-permeable inhibitor of ICE-like protease activity to examine in vivo whether post-receptor signaling of TNF and CD95 are fully independent processes. Mice pretreated with the inhibitor, Z-VAD-fluoromethylketone (FMK) were dose-dependently protected from liver injury caused by CD95 activation as determined by plasma alanine aminotransferase and also from hepatocyte apoptosis assessed by DNA fragmentation (ID50=0.1 mg/kg). A dose of 10 mg/kg protected mice also from liver injury induced by TNF-α. Similar results were found when apoptosis was initiated via TNF-α or via CD95 in primary murine hepatocytes (IC50=1.5 nM) or in various human cell lines. In addition to prevention, an arrest of cell death by Z-VAD-FMK was demonstrated in vivo and in vitro after stimulation of apoptosis receptors. These findings show in vitro and in vivo in mammals that CD95 and the TNF-α receptor share a distal proteolytic apoptosis signal

Stereoselectivity of the enantiomers of trihexyphenidyl and its methiodide at muscarinic receptor subtypes.

High stereoselectivity was observed for the enantiomers of trihexyphenidyl and trihexyphenidyl methiodide at muscarinic M1-receptors in field-stimulated rabbit vas deferens and at M2 alpha- and M2 beta-receptors in guinea-pig atrium and ileum, respectively. Considerably higher affinities (up to 1700-fold) were found for the (R)-(-)-enantiomers. The stereochemical demands made by the muscarinic receptor subtypes were most stringent at the M1-receptors. The (R)-(-)-enantiomers were found to be potent M1-selective antagonists (pA2 = 10.1/10.6). They showed a 91- and 45-fold selectivity for M1- over M2 alpha-receptors, respectively.In VitroJournal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Catalytically Active Silica Nanoparticle-Based Supramolecular Architectures of Two Proteins – Cellobiose Dehydrogenase and Cytochrome <i>c</i> on Electrodes

Artificial nanobiomolecular architectures that follow natural examples in protein assembly become more and more important from basic and applied points of view. Our study describes the investigation on cellobiose dehydrogenase (CDH), cytochrome <i>c</i> (cyt <i>c</i>), and silica nanoparticles (SiNP's) for the construction of fully catalytically active supramolecular architectures on electrodes. We report on intraprotein, interprotein, and direct electron-transfer reaction cascades of cellobiose dehydrogenase and cytochrome <i>c</i> immobilized in multiple supramolecular layers. Carboxy-modified SiNP's are used to provide an artificial matrix, which enables protein arrangement in an electroactive form. Direct and interprotein electron transfer has been established for a two-protein system with CDH and cyt <i>c</i> in a layered architecture for the first time. We also highlight that the glycosylation of CDH and the silica nanoparticle size play key roles in the mode of operation in such a complex system. The response of the specific substrate, here lactose, can be tuned by the number of immobilized nanobiomolecular layers

Stereoselectivity of the interaction of muscarinic antagonists with their receptors

The stereoselectivity of the interaction with muscarinic receptors of enantiomers of a series of chiral antagonists is receptor subtype dependent. There is no overall relationship between stereoselectivity and receptor affinity. Depending on the antagonist studied, receptor stereoselectivity may indeed reflect: (1) the weakening or loss of a single interaction involving one of the four groups bound to the asymmetric carbon; (2) steric hindrance preventing optimum interaction of the low affinity steroisomer with the receptor; and/or (3) the inversion of the relative positions of two moieties of the ligand with similar structural and electronic properties i.e. comparable affinities for the two corresponding subsites in the receptor.SCOPUS: cp.jinfo:eu-repo/semantics/publishe

Modulating ADME Properties by Fluorination: MK2 Inhibitors with Improved Oral Exposure.

MK2, MAP-activated protein kinase 2, plays an important role in the regulation of innate immune response as well as in cell survival upon DNA damage. Despite its potential in the treatment of inflammation and cancer, up to date no MK2 low molecular weight inhibitor reached the clinic, mainly because of inadequate ADME properties of the developed inhibitors. In this paper we describe an approach based on specifically placed fluorine within a recently described pyrrole-based MK2 inhibitor scaffold for manipulation of its physicochemical and ADME properties. While keeping the target potency, the novel fluoro-derivatives showed not only improved permeability but also enhanced solubility and reduced in vivo clearance leading to significantly increased oral exposure