Synthesis of (−)-Epi-Indolactam V by an Intramolecular Buchwald–Hartwig C–N Coupling Cyclization Reaction

The synthetic efforts toward the concise synthesis of (−)-indolactam V from simple and commercially available starting materials using palladium- and copper-catalyzed intramolecular N-arylation strategy for the elaboration of the requisite nine-membered lactam ring as the key step are described. The incorporation of a turn-inducing structural element along the linear precursor was fundamental to achieve the heterocyclization step as well as obtain the correct regio- and chemoselectivity. The stereoselective nature in the C–N coupling cyclization reaction is interpreted in terms of minimization of allylic strain at the transition state for the palladium-amido complex formation. Meanwhile, the synthesis of the (−)-epi-indolactam V and its enantiomer have been accomplished

Asymmetric Total Synthesis of All Rugulovasine Stereoisomers and Preliminary Evaluation of Their Biological Properties

A unified enantioselective synthesis and the biological evaluation of all rugulovasine stereoisomers are reported. The syntheses are centered on the divergent and stereochemical modular combination of each enantiomer of 4-amino Uhle's ketone and a methacrylate derivative to build the unsaturated oxaspirolactone moiety by the Dreiding-Schmidt reaction, followed by Fukuyama alkylation to afford the required N-methyl secondary amine in excellent yield. The modularity of this divergent approach, the diastereoselectivities of the reactions, and the late-stage site-selective methylation permit the rapid asymmetric syntheses of all rugulovasine stereoisomers, including the first total syntheses of optically pure (+)- and (−)-rugulovasine B and their trideuteromethylated derivatives. All enantiopure stereoisomers of rugulovasine were tested for their binding affinities to dopamine, serotonin, and adrenergic neuroreceptors, revealing their preferred selectivity for the serotonin 1 A receptor

Palladium(II)-Catalyzed Cross-Dehydrogenative Coupling (CDC) of N-Phthaloyl Dehydroalanine Esters with Simple Arenes: Stereoselective Synthesis of Z-Dehydrophenylalanine Derivatives

Pd(II)-catalyzed cross-dehydrogenative coupling (CDC) of methyl N-phthaloyl dehydroalanine esters with simple aromatic hydrocarbons is reported. The reaction, which involves the cleavage of two sp(2) C-H bonds followed by C-C bond formation, stereoselectively generates highly valuable Z-dehydrophenylalanine skeletons in a practical, versatile, and atom economical manner. In addition, a perfluorinated product was expediently converted into important nonproteinogenic amino acid building blocks through copper-catalyzed conjugate additions of boron, silicon, and hydride moieties

Rainfall induced landslides in December 2004 in south-western Umbria, central Italy: types, extent, damage and risk assessment

International audienceThe autumn of 2004 was particularly wet in Umbria, with cumulative rainfall in the period from October to December exceeding 600 mm. On 4?6 December and on 25?27 December 2004, two storms hit the Umbria Region producing numerous landslides, which were abundant near the town of Orvieto where they affected volcanic deposits and marine sediments. In this work, we document the type and abundance of the rainfall-induced landslides in the Orvieto area, in south-western Umbria, we study the rainfall conditions that triggered the landslides, including the timing of the slope failures, we determine the geotechnical properties of the failed volcanic materials, and we discuss the type and extent of damage produced by the landslides. We then use the recent event landslide information to test a geomorphological assessment of landslide hazards and risk prepared for the village of Sugano, in the Orvieto area. Based on the results of the test, we update the existing landslide hazards and risk scenario for extremely rapid landslides, mostly rock falls, and we introduce a new landslide scenario for rapid and very rapid landslides, including soil slides, debris flows and debris avalanches

Localization of nuclear actin in nuclear lipid microdomains of liver and hepatoma cells: Possible involvement of sphingomyelin metabolism

Nuclear actin has been implicated in different nuclear functions. In this work, its localization in nuclear membrane, chromatin and nuclear lipid microdomains was investigated. The implication of sphingomyelin metabolism was studied. Nuclear membrane, chromatin and nuclear lipid microdomains were purified from hepatocyte nuclei and H35 human hepatoma cell nuclei. The presence of \u3b2-actin was analyzed with immunoblotting by using specific antibodies. Sphingomyelinase, sphingomyelin-synthase, and phosphatidylcholine-specific phospholipase C activities were assayed by using radioactivity sphingomyelin and phosphatidylcholine as substrate. The results showed that \u3b2-actin is localized in nuclear lipid microdomains and it increases in cancer cells. Evidence is provided to the difference of phosphatidylcholine and sphingomyelin metabolism in various subnuclear fractions of cancer cell nuclei compared with normal cells. Our findings show increase of sphingomyelin-synthase and inhibition of sphingomyelinase activity only in nuclear lipid microdomains. Nuclear lipid microdomains, constituted by phosphatidylcholine, sphingomyelin and cholesterol, play a role as platform for \u3b2-actin anchoring. Possible role of sphingomyelin metabolism in cancer cells is discussed

An Italian Multicenter Perspective Harmonization Trial for the Assessment of MET Exon 14 Skipping Mutations in Standard Reference Samples

Lung cancer remains the leading cause of cancer deaths worldwide. International societies have promoted the molecular analysis of MET proto-oncogene, receptor tyrosine kinase (MET) exon 14 skipping for the clinical stratification of non-small cell lung cancer (NSCLC) patients. Different technical approaches are available to detect MET exon 14 skipping in routine practice. Here, the technical performance and reproducibility of testing strategies for MET exon 14 skipping carried out in various centers were evaluated. In this retrospective study, each institution received a set (n = 10) of a customized artificial formalin-fixed paraffin-embedded (FFPE) cell line (Custom METex14 skipping FFPE block) that harbored the MET exon 14 skipping mutation (Seracare Life Sciences, Milford, MA, USA), which was previously validated by the Predictive Molecular Pathology Laboratory at the University of Naples Federico II. Each participating institution managed the reference slides according to their internal routine workflow. MET exon 14 skipping was successfully detected by all participating institutions. Molecular analysis highlighted a median Cq cut off of 29.3 (ranging from 27.1 to 30.7) and 2514 (ranging from 160 to 7526) read counts for real-time polymerase chain reaction (RT-PCR) and NGS-based analyses, respectively. Artificial reference slides were a valid tool to harmonize technical workflows in the evaluation of MET exon 14 skipping molecular alterations in routine practice

Brief communication: Evidence of pathology on the frontal bone from Gongwangling

The hominid fossil from Gongwangling (Lantian) is well known and described (Woo, [1965] Scientia Sinca 14:1032–1036; Woo [1966] Curr. Anthropol. 7:83–86; Wu and Dong [1985] in R Wu and JW Olsen (eds.): Palaeoanthropology and Paleolithic Archaeology in the People's Republic of China [New York: Academic Press, pp. 79–89]; Wu and Poirier [1995] Human Evolution in China: A Metric Description of the Fossils and a Review of the Sites [Oxford: Oxford University Press]). However, evidence of pathology on the frontal bone has been previously unreported. Two lesions occur on the right supraorbital region that can be distinguished from marks of erosion prevalent on this specimen. These are discrete and irregularly shaped, with evidence of secondary bone formation surrounding them. The cause of the condition is unclear. Possibilities include trauma or abscess from an unspecified infection. Am J Phys Anthropol 102:565–568, 1997. © 1997 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37681/1/10_ftp.pd