Drug–Membrane Interaction on Immobilized Liposome Chromatography Compared to Immobilized Artificial Membrane (IAM), Liposome/Water,and Octan‐1‐ol/Water Systems

The objective of this study was to investigate drug–membrane interaction by immobilized liposome chromatography (ILC; expressed as lipophilicity index log K_s) and the comparison with lipophilicity indices obtained by liposome/H₂O, octan‐1‐ol/H₂O, and immobilized artificial membrane (IAM) systems. A set of structurally diverse monofunctional compounds and drugs (nonsteroidal anti‐inflammatory drugs and β‐blockers) were selected in this study. This set of solutes consists of basic or acidic functionalities which are positively or negatively charged at physiological pH 7.4. No correlation was found between log K_s from ILC and lipophilicity indices from any of the other membrane model systems for the whole set of compounds. For structurally related compounds, significant correlations could be established between log K_s from ILC and lipophilicity indices from IAM chromatography and octan‐1‐ol/H₂O. However, ILC and liposome/H₂O systems only yield parallel partitioning information for structurally related large molecules. For hydrophilic compounds, the balance between electrostatic and hydrophobic interactions dominating drug partitioning is different in these two systems.     

Rapid and efficient microwave-assisted synthesis of 5-amino-3-aralkoxy(methoxy)amino-1,2,4-oxadiazoles

The microwave-assisted synthesis of 5-amino-3-aralkoxy(methoxy)amino-1,2,4-oxadiazoles starting from N¹-aralkoxy-(methoxy)-N³-cyano-O-phenylisoureas and hydroxylamine is described. N¹-Aralkoxy(methoxy)-N³-cyano-O-phenylisoureas are readily accessible by treatment of diphenyl N-cyanimidocarbonate with O-substituted hydroxylamines.     

Ferrocenyl‐Coupled N‐Heterocyclic Carbene Complexes of Gold(I): A Successful Approach to Multinuclear Anticancer Drugs

Four gold(I) carbene complexes featuring 4‐ferrocenyl‐substituted imidazol‐2‐ylidene ligands were investigated for antiproliferative and antivascular properties. They were active against a panel of seven cancer cell lines, including multidrug‐resistant ones, with low micromolar or nanomolar IC₅₀ (72 h) values, according to their lipophilicity and cellular uptake. The delocalized lipophilic cationic complexes 8 and 10 acted by increasing the reactive oxygen species in two ways: through a genuine ferrocene effect and by inhibiting the thioredoxin reductase. Both complexes gave rise to a reorganization of the F‐actin cytoskeleton in endothelial and melanoma cells, associated with a G1 phase cell cycle arrest and a retarded cell migration. They proved antiangiogenic in tube formation assays with endothelial cells and vascular‐disruptive on real blood vessels in the chorioallantoic membrane of chicken eggs. Biscarbene complex 10 was also tolerated well by mice where it led to a volume reduction of xenograft tumors by up to 80 %.     

Comparisons of NMR spectral quality and success in crystallization demonstrate that NMR and X-ray crystallography are complementary methods for small protein structure determination

X-ray crystallography and NMR spectroscopy provide the only sources of experimental data from which protein structures can be analyzed at high or even atomic resolution. The degree to which these methods complement each other as sources of structural knowledge is a matter of debate; it is often proposed that small proteins yielding high quality, readily analyzed NMR spectra are a subset of those that readily yield strongly diffracting crystals. We have examined the correlation between NMR spectral quality and success in structure determination by X-ray crystallography for 159 prokaryotic and eukaryotic proteins, prescreened to avoid proteins providing polydisperse and/or aggregated samples. This study demonstrates that, across this protein sample set, the quality of a protein's [15N-1H]-heteronuclear correlation (HSQC) spectrum recorded under conditions generally suitable for 3D structure determination by NMR, a key predictor of the ability to determine a structure by NMR, is not correlated with successful crystallization and structure determination by X-ray crystallography. These results, together with similar results of an independent study presented in the accompanying paper (Yee, et al., J. Am. Chem. Soc., accompanying paper), demonstrate that X-ray crystallography and NMR often provide complementary sources of structural data and that both methods are required in order to optimize success for as many targets as possible in large-scale structural proteomics efforts.     

Mass Spectrometric Observation of Doubly Charged Alkaline‐Earth Argon Ions

Doubly charged diatomic ions MAr²⁺ where M=Mg, Ca, Sr or Ba have been observed by mass spectrometry with an inductively coupled plasma ion source. Abundance ratios are quite high, 0.1 % for MgAr²⁺, 0.4 % for CaAr²⁺, 0.2 % for SrAr²⁺ and 0.1 % for BaAr²⁺ relative to the corresponding doubly charged atomic ions M²⁺. It is assumed that these molecular ions are formed through reactions of the doubly charged metal ions with neutral argon atoms within the ion source. Bond dissociation energies (D₀) were calculated and agree well with previously published values. The abundance ratios MAr⁺/M⁺ and MAr²⁺/M²⁺ generally follow the predicted bond dissociation energies with the exception of MgAr²⁺. Mg²⁺ should form the strongest bond with Ar [D₀ (MgAr²⁺)=124 to 130 kJ mol^?1] but its relative abundance is similar to that of the weakest bound BaAr²⁺ (D₀=34 to 42 kJ mol^?1). The relative abundances of the various MAr²⁺ ions are higher than those expected from an argon plasma at T=6000 K, indicating that collisions during ion extraction reduce the abundance of the MAr²⁺ ions relative to the composition in the source. The corresponding singly charged MAr⁺ ions are also observed but occur at about three orders of magnitude lower intensity than MAr²⁺.     

Dehydration of Alkanones by Bare FeO+ Involves the ω/(ω − 1) Positions: Exclusion of Iron Carbenes as Intermediates. Preliminary Communication

Fourier-transform ion-cyclotron-resonance (FTICR) mass spectrometry has been used to uncover the mechanisms by which FeO⁺ dehydrates heptan-4-one ( 5a ) and nonan-5-one ( 6a ) in the gas phase. The study of isotopomeric ketones provides evidence that H₂O loss is not due to a 1,1-elimination, thus ruling out the intermediacy of high-valent iron-carbene species. Rather, H₂O is generated in a formal 1,2-elimination involving the ω/ω ? 1 positions of the alkyl chain (‘remote C? H bond activation’). In the consecutive alkene/H₂O elimination, the olefins (ethylene from 5a and propene from 6a ) originate from the terminal part of one alkyl chain, and the H-atom is transferred to the FeO⁺ moiety in the course of this process, builds up together with an H-atom from the ω/ω-1 position of the other alkyl chain the H₂O molecule. In either case, the O-atom of H₂O is provided by the FeO⁺ species.     

A ditopic calix[6]arene ligand with N-methylimidazole and 1,2,3-triazole substituents: synthesis and coordination with Zn(II) cations

The first member of a new class of ditopic calix[6]arene has been synthesized, which is decorated with three N-methylimidazoles at the small rim and three 1,4-disubstituted-1,2,3-triazoles at the large rim. The coordination of a first Zn(II) cation selectively takes place at the small rim. Addition of a second equivalent results in the complexation of the three triazoles, providing a rare example of 1,2,3-triazole ligands embedded within a supramolecular system.