Structure of the alpha-homo-DNA:RNA duplex and the function of twist and slide to catalogue nucleic acid duplexes

High-resolution NMR studies of an alpha-homo-DNA:RNA duplex reveal the formation of a right-handed parallel-oriented helix. It differs significantly from a standard A- or B-type helix by a small twist value (26.2 degrees ), which leads to a helical pitch of 13.7 base pairs per helical turn, a negative inclination (-1.78 Angstrom) and a large x displacement (5.90 Angstrom). The rise (3.4 Angstrom) is similar to that found in B-DNA. The solution of this new helix structure has stimulated us to develop a mathematical and geometrical model based on slide and twist parameters to describe nucleic acid duplexes. All existing duplexes can be positioned within this landscape, which can be used to understand the helicalization process.     

Bioinformatic analysis of xenobiotic reactive metabolite target proteins and their interacting partners

Background  

Protein covalent binding by reactive metabolites of drugs, chemicals and natural products can lead to acute cytotoxicity. Recent rapid progress in reactive metabolite target protein identification has shown that adduction is surprisingly selective and inspired the hope that analysis of target proteins might reveal protein factors that differentiate target- vs. non-target proteins and illuminate mechanisms connecting covalent binding to cytotoxicity.     

Chiral poly(ureidophthalimide) foldamers in water

Poly(ureidophthalimide)s decorated with hydrophilic side chains, that ensure solubility in aqueous media, have been synthesized and characterized by UV/Vis and circular dichroism (CD) spectroscopy. Temperature and concentration dependent CD measurements in water have revealed an almost temperature and concentration independent Cotton effect, indicative for a strong intramolecular organization. Similar studies in THF demonstrate the dynamic nature of the secondary architecture, a characteristic of foldamers. In addition, the bisignated Cotton effect in water is opposite in sign to that in THF, suggestive for a solvent-dependent preference for one helical handedness. Mixing experiments prove the dominance of water in determining the handedness of the helical architecture. The solvent allows for control over the helical architecture and thus governs the supramolecular synthesis.     

Direct quantification of steroid glucuronides in human urine by liquid chromatography-electrospray tandem mass spectrometry

A method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the direct quantification of glucuronides of testosterone (TG), epitestosterone (EPG), androsterone (AG) and etiocholanolone (ETG) has been developed. The method allowed for the direct determination of these analytes avoiding hydrolysis and derivatization, which are usual steps in commonly used methods based on gas chromatography-mass spectrometry (GC-MS). The electrospray ionization and the product ion spectra of the glucuronides have been studied in order to obtain the most specific transitions. The use of the selected transitions is necessary for the determination of the analytes at low ng/ml concentration levels. Two different approaches have been tested for sample preparation: direct injection after filtration and acidic liquid-liquid extraction (LLE) with ethyl acetate. Both approaches have been validated obtaining satisfactory values for accuracy and precision with limits of detection lower than 1 ng/ml for TG and EPG. Ion suppression was more pronounced after LLE probably due to the concentration of interferences from acidic urine. The applicability of the method has been checked by the analysis of 40 urine samples. The results were compared with those obtained with the common GC-MS method. Results have shown a good correlation between both methods with correlation coefficients higher than 0.97. A slope close to 1 was obtained for all analytes except for AG possibly due to losses during the extraction process prior to GC-MS.     

Synthesis of 6-methyl-6H-indolo[3,2-c]isoquinoline and 6-methyl-6H-indolo[2,3-c]isoquinoline: two new unnatural isoquinoline isomers of the cryptolepine series

11H-indolo[3,2-c]isoquinoline has been synthesized in two steps starting from 4-bromoisoquinoline and 2-bromoaniline via a selective Buchwald-Hartwig reaction followed by a Pd-catalyzed intramolecular direct arylation involving C(sp²)-H activation. The synthesis of 7H-indolo[2,3-c]isoquinoline was achieved by a combination of a Suzuki reaction with an intramolecular nitrene insertion reaction starting from 4-bromoisoquinoline and {2-[(2,2-dimethylpropanoyl)amino]phenyl}boronic acid. Selective methylation of the tetracyclic skeletons yielded the title compounds 6-methyl-6H-indolo[3,2-c]isoquinoline and 6-methyl-6H-indolo[2,3-c]isoquinoline, which have never been described in the literature before.     

A Mechanistic Investigation of the Visible‐Light Photocatalytic Trifluoromethylation of Heterocycles Using CF3I in Flow

Photocatalytic radical trifluoromethylation strategies have impacted the synthesis of trifluoromethyl‐containing molecules. However, mechanistic aspects concerning such transformations remain poorly understood. Here, we describe in detail the mechanism of the visible‐light photocatalytic trifluoromethylation of N‐methylpyrrole with gaseous CF₃I in flow. The use of continuous‐flow microreactor technology allowed for the determination of different important parameters with high precision (e.g., photon flux, quantum yield, reaction rate constants) and for the handling of CF₃I in a convenient manner. Our data indicates that the reaction occurs through a reductive quenching mechanism and that there is no radical chain process present.