NMR Fingerprints of the Drug‐like Natural‐Product Space Identify Iotrochotazine A: A Chemical Probe to Study Parkinson’s Disease

The NMR spectrum of a mixture of small molecules is a fingerprint of all of its components. Herein, we present an NMR fingerprint method that takes advantage of the fact that fractions contain simplified NMR profiles, with minimal signal overlap, to allow the identification of unique spectral patterns. The approach is exemplified in the identification of a novel natural product, iotrochotazine A ( 1 ), sourced from an Australian marine sponge Iotrochota sp. Compound 1 was used as a chemical probe in a phenotypic assay panel based on human olfactory neurosphere‐derived cells (hONS) from idiopathic Parkinson’s disease patients. Compound 1 at 1 μM was not cytotoxic but specifically affected the morphology and cellular distribution of lysosomes and early endosomes.     

Structural characterizations of lipids A by MS/MS of doubly charged ions on a hybrid linear ion trap/orbitrap mass spectrometer

Here, a new 'one pot' and fast approach is described, based on electrospray ionization (ESI) of negative ions by using a hybrid linear ion trap/orbitrap mass spectrometer (LTQ/orbitrap) for MS and MS/MS analysis. By this method the distribution of the primary and secondary acyl residues of the intact lipid A is inferred by analysis of the ESI spectra measured in positive and negative mode. The analysis of these data allows an unequivocal assignment of the fatty acid distribution. This methodology was successfully tested on two different lipid A with known structures, deriving from the Agrobacterium tumefaciens and Escherichia coli lipopolysaccharides (LPS).     

External Micro-PIXE Measurements: Preliminary Results on Volcanic Rocks from Nyiragongo Volcano

The external microbeam facility at the 3 MV Tandetron accelerator of the LABEC Laboratory of INFN in Florence has been used to determine, by PIXE, major, minor and trace element abundances of minerals and groundmass in the lavas from the active Nyiragongo Volcano (Democratic Republic of Congo), which is well known for its lava lake intra-crateric activity [e.g. 1, 2]. During the last eruption of this volcano (January, 2002), two main flows entered the Goma town producing major devastation, forcing the rapid exodus of about 300,000 people and causing the death of 150 persons [3]. After this eruption, the interest of the scientific community on this volcanic area suddenly increased. In this respect, determination of major and trace element abundances in mineral phases and groundmass of lavas may allow to constrain the evolution of magma within the volcanic system from a quantitative view point, thus helping to better understand the way this volcano works. PIXE measurements have been performed in a two-detector setup that makes it possible to simultaneously detect and quantify all elements from Na to the heaviest ones; possible compositional zoning effects in the crystals can also be reliably measured thanks to the good space resolution of the microbeam facility (better than 10 μm) and to the possibility of performing one- and bi-dimensional scans over the areas of interest. Concentration maps of all elements can be obtained, both on-line and a posteriori: the data are collected with a list-mode acquisition system, which allows the distribution of any detected element to be reconstructed after completing the scan.     

Energetic proton emission in heavy ion collisions at intermediate energy: Pre-equilibrium and cooperative effects

Energetic proton emission has been investigated as a function of the centrality in the reaction ⁵⁸Ni + ⁵⁸Ni at 30 AMeV. Protons with energy extending up to a relevant fraction of the total available energy in the reaction were measured and studied. The dependence on the reaction centrality has been extensively investigated and data have been compared with the results of microscopic transport calculations. The more striking observation concerns the extremely energetic proton (E^NN _P ≥ 130 MeV) multiplicity which is found to increase almost quadratically with the number of participant nucleons thus indicating the onset of a mechanism beyond one and two-body dynamics.     

Tandem Allylboration–Prins Reaction for the Rapid Construction of Substituted Tetrahydropyrans: Application to the Total Synthesis of (−)‐Clavosolide A

Tetrahydropyrans are common motifs in natural products and have now been constructed with high stereocontrol through a three‐component allylboration‐Prins reaction sequence. This methodology has been applied to a concise (13 steps) and efficient (14 % overall yield) synthesis of the macrolide (?)‐clavosolide A. The synthesis also features an early stage glycosidation reaction to introduce the xylose moiety and a lithiation‐borylation reaction to attach the cyclopropyl‐containing side chain.     

Dendronized scorpionate complexes of molybdenum in low and high oxidation states

Tridentate (L(3)) and bidentate (L(2)) poly(pyrazolyl)methane ligands (Gn-dend)OCH(2)C(pz)(3) (1-4) and (Gn-dend)CH(3,5-Me(2)pz)(2) (pz = pyrazol-1-yl) have been used to synthesize the molybdenum(0) complexes [Mo(CO)(3)(L(3))] (G0-G3, 5-8), [Mo(CO)(4)(L(2))] (G0-G1, 13-14), and [Mo(CO)(3)(NCMe)(L(2))] (G0, 15), and the molybdenum(VI) complexes [MoCl(2)O(2)(L(2))] (9-12). The G0-G3 prefixes represent the generation of poly(aryl ether) dendrons in which the metal complexes are embedded. The molecular structures of compounds 13 and 15 have been determined by X-ray diffraction studies and the hydrodynamic radii of tricarbonyl complexes 5-8 calculated by diffusion-ordered NMR spectroscopy (DOSY). Molybdenum(VI) compounds 9-12 have also been evaluated as catalysts for olefin epoxidation, showing comparable but inferior performances than ligand-free MoCl(2)O(2), probably because of the labile coordination of L(2).     

Histidine‐Rich Oligopeptides To Lessen Copper‐Mediated Amyloid‐β Toxicity

Brain copper imbalance plays an important role in amyloid‐β aggregation, tau hyperphosphorylation, and neurotoxicity observed in Alzheimer's disease (AD). Therefore, the administration of biocompatible metal‐binding agents may offer a potential therapeutic solution to target mislocalized copper ions and restore metallostasis. Histidine‐containing peptides and proteins are excellent metal binders and are found in many natural systems. The design of short peptides showing optimal binding properties represents a promising approach to capture and redistribute mislocalized metal ions, mainly due to their biocompatibility, ease of synthesis, and the possibility of fine‐tuning their metal‐binding affinities in order to suppress unwanted competitive binding with copper‐containing proteins. In the present study, three peptides, namely HWH , HK^CH , and HAH , have been designed with the objective of reducing copper toxicity in AD. These tripeptides form highly stable albumin‐like complexes, showing higher affinity for Cu^II than that of Aβ(1‐40). Furthermore, HWH , HK^CH , and HAH act as very efficient inhibitors of copper‐mediated reactive oxygen species (ROS) generation and prevent the copper‐induced overproduction of toxic oligomers in the initial steps of amyloid aggregation in the presence of Cu^II ions. These tripeptides, and more generally small peptides including the sequence His‐Xaa‐His at the N‐terminus, may therefore be considered as promising motifs for the future development of new and efficient anti‐Alzheimer drugs.     

CH/pi interactions involving aromatic amino acids: refinement of the CHARMM tryptophan force field

High-level ab initio calculations have been carried out to study weak CH/pi interactions and as a check of the CHARMM force field for aromatic amino acids. Comparisons with published data indicate that the MP2/cc-pVTZ level of theory is suitable for calculations of CH/pi interaction, including the T-shape benzene dimer. This level of theory was, therefore, applied to investigate CH/pi interactions between ethene or cis-2-butene and benzene in a variety of orientations. In addition, complexes between ethene and a series of model compounds (toluene, methylindole and p-cresol) representing the aromatic amino acids were studied motivated by the presence of CH/pi interactions in biological systems. Ab initio binding energies were compared to the binding energies obtained with the CHARMM22 force field. In the majority of orientations, CHARMM22 reproduces the preferred binding modes, with excellent agreement for the benzene dimer. Small discrepancies found in the calculations involving methylindole along with a survey of published thermodynamic data for the aromatic amino acids prompted additional optimization of the tryptophan force field. Partial atomic charges, Lennard-Jones parameters, and force constants were improved to obtain better intra- and intermolecular properties, with significant improvements obtained in the reproduction of experimental heats of sublimation for indole and free energies of aqueous solvation for methylindole.