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A new ultrafast and high-throughput mass spectrometric approach for the therapeutic drug monitoring of the multi-targeted anti-folate pemetrexed in plasma from lung cancer patients

An analytical assay has been developed and validated for ultrafast and high-throughput mass spectrometric determination of pemetrexed concentrations in plasma using matrix assisted laser desorption/ionization–triple quadrupole–tandem mass spectrometry. Patient plasma samples spiked with the internal standard methotrexate were measured by multiple reaction monitoring. The detection limit was 0.4 fmol/μL, lower limit of quantification was 0.9 fmol/μL, and upper limit of quantification was 60 fmol/μL, respectively. Overall observed pemetrexed concentrations in patient samples ranged between 8.7 (1.4) and 142.7 (20.3)?pmol/μL (SD). The newly developed mass spectrometric assay is applicable for (routine) therapeutic drug monitoring of pemetrexed concentrations in plasma from non-small cell lung cancer patients.     

Rydberg-valence mixing in the carbon 1s near-edge X-ray absorption fine structure spectra of gaseous alkanes

We have acquired high-resolution carbon 1s near-edge X-ray absorption fine structure (NEXAFS) spectra of methane, ethane, propane, isobutane, and neopentane. These experimental measurements are complemented by high-quality ab initio calculations, performed with the improved virtual orbital approximation. The degree and character of Rydberg-valence mixing in the preedge of the NEXAFS spectra of these species is explored. Significant Rydberg-valence mixing only occurs when there are excited states of valence sigma(C-H) character that have the appropriate symmetry to interact with excited states of Rydberg character. Our results show that this mixing is only present when there are C-H bonds to the core excited carbon atom.     

Photoswitching the Efficacy of a Small‐Molecule Ligand for a Peptidergic GPCR: from Antagonism to Agonism

For optical control of GPCR function, we set out to develop small‐molecule ligands with photoswitchable efficacy in which both configurations bind the target protein but exert distinct pharmacological effects, that is, stimulate or antagonize GPCR activation. Our design was based on a previously identified efficacy hotspot for the peptidergic chemokine receptor CXCR3 and resulted in the synthesis and characterization of five new azobenzene‐containing CXCR3 ligands. G protein activation assays and real‐time electrophysiology experiments demonstrated photoswitching from antagonism to partial agonism and even to full agonism (compound VUF16216). SAR evaluation suggests that the size and electron‐donating properties of the substituents on the inner aromatic ring are important for the efficacy photoswitching. These compounds are the first GPCR azo ligands with a nearly full efficacy photoswitch and may become valuable pharmacological tools for the optical control of peptidergic GPCR signaling.     

Phase behavior and microstructure of microemulsions with a room-temperature ionic liquid as the polar phase

Microemulsions of nonionic alkyl oligoethyleneoxide (CiEj) surfactants, alkanes, and ethylammonium nitrate (EAN), a room-temperature ionic liquid, have been prepared and characterized. Studies of phase behavior reveal that EAN microemulsions have many features in common with corresponding aqueous systems, the primary difference being that higher surfactant concentrations and longer surfactant tailgroups are required to offset the decreased solvophobicity the surfactant molecules in EAN compared with water. The response of the EAN microemulsions to variation in the length of the alkane, surfactant headgroup, and surfactant tailgroup has been found to parallel that observed in aqueous systems in most instances. EAN microemulsions exhibit a single broad small-angle X-ray scattering peak, like aqueous systems. These are well described by the Teubner-Strey model. A lamellar phase was also observed for surfactants with longer tails at lower temperatures. The scattering peaks of both microemulsion and lamellar phases move to lower wave vector on increasing temperature. This is ascribed to a decrease in the interfacial area of the surfactant layer. Phase behavior, small-angle X-ray scattering, and conductivity experiments have allowed the weakly to strongly structured transition to be identified for EAN systems.     

Step-wise and pre-organization induced synthesis of a crossed alkene-bridged nisin Z DE-ring mimic by ring-closing metathesis

This paper describes two approaches for the synthesis of a crossed alkene-bridged mimic of the thioether ring system of the nisin Z DE-fragment. The first approach comprised the stepwise total synthesis featuring a cross metathesis and a macrolactamization on a solid support followed by a ring-closing metathesis in solution. Via this route the title compound was obtained in an overall yield of 7% (85% on average for 16 reaction steps). In the second approach, the linear precursor peptide was subjected to ring-closing metathesis and the bicyclic peptide with the correct side chain connectivity pattern was obtained in yields up to 95%. The preferred formation of the bicyclic crossed alkene-bridged mimic of the DE-ring suggests a favorable pre-organization of the linear precursor peptide.     

Bis‐Calix[4]arenes: From Ligand Design to the Directed Assembly of a Metal–Organic Trigonal Antiprism

Calix[4]arenes (C[4]s) are versatile platforms for the construction of polymetallic clusters containing paramagnetic metal ions. Synthetic modification at the C[4] methylene bridge allows for the design of bis‐C[4]s that, depending on the linker employed, can be used to either dictate which clusters can be formed or direct the assembly of a new metal–organic polyhedron (MOP). The assembly resulting from the latter approach displays thermal stability and uptake of N₂ or H₂ gas, confirming that this is a viable route to the synthesis of new, functional supramolecular architectures.     

Enantioselective synthesis of chiral porphyrin macrocyclic hosts and kinetic enantiorecognition of viologen guests

The construction of macromolecular hosts that are able to thread chiral guests in a stereoselective fashion is a big challenge. We herein describe the asymmetric synthesis of two enantiomeric C₂-symmetric porphyrin macrocyclic hosts that thread and bind different viologen guests. Time-resolved fluorescence studies show that these hosts display a factor 3 kinetic preference (ΔΔG^‡_on = 3 kJ mol⁻¹) for threading onto the different enantiomers of a viologen guest appended with bulky chiral 1-phenylethoxy termini. A smaller kinetic selectivity (ΔΔG^‡_on = 1 kJ mol⁻¹) is observed for viologens equipped with small chiral sec-butoxy termini. Kinetic selectivity is absent when the C₂-symmetric hosts are threaded onto chiral viologens appended with chiral tails in which the chiral moieties are located in the centers of the chains, rather than at the chain termini. The reason is that the termini of the latter guests, which engage in the initial stages of the threading process (entron effect), cannot discriminate because they are achiral, in contrast to the chiral termini of the former guests. Finally, our experiments show that the threading and de-threading rates are balanced in such a way that the observed binding constants are highly similar for all the investigated host–guest complexes, i.e. there is no thermodynamic selectivity.

Chiral guests display kinetic stereoselective threading through chiral porphyrin cages if their chirality is located at the chain ends and not in the centers, supporting the previously reported entron effect of threading.     

Worst VaR scenarios with given marginals and measures of association

This paper studies the problem of finding best-possible upper bounds on the Value-at-Risk for a function of two random variables when the marginal distributions are known and additional nonparametric information on the dependence structure, such as the value of a measure of association, is available. The same problem for the Tail-Value-at-Risk is also briefly discussed.