Ernst Schering Foundation symposium proceedings最新文献

G protein-coupled receptors (GPCRs) fulfil a broad diversity of physiological functions in areas such as neurotransmission, respiration, cardiovascular action, pain and more. Consequently, they are considered as the most successful group of therapeutic targets on the pharmaceutical market, and the search for compounds that interfere with GPCR function in a specific and selective way is a major focus of the pharmaceutical industry. High Content Screening (HCS), a combination of fluorescence microscopic imaging and automated image analysis, has become a frequently employed tool to study test compound effects in cellular disease modelling systems. One way to functionally analyse the effect of test compounds on GPCRs by HCS relies on the broadly observed phenomenon of desensitisation. Agonist stimulation of most GPCRs leads to their intracellular phosphorylation and subsequent internalisation, resulting in the termination of receptor signalling and the seclusion of the GPCR from further extracellular stimulation. Complementary to other functional GPCR drug discovery assays, GPCR internalisation assays enable a desensitisation-focussed pharmacological analysis of test compounds.

From the point of view of a participant observer, I tell the discovery stories of trimeric G-proteins and GPCRs, beginning in the 1970s. As in most such stories, formidable obstacles, confusion, and mistakes make eventual triumphs even more exciting. Because these pivotally important signaling molecules were discovered before the recombinant DNA revolution, today's well-trained molecular biologist may find it amazing that we learned anything at all.

Recent developments in the construction of microstructured reaction devices and their wide-ranging applications in many different areas of chemistry suggest that microreactors may significantly impact the way chemists conduct experiments. Miniaturizing reactions offers many advantages for the synthetic organic chemist: high-throughput scanning of reaction conditions, precise control of reaction variables, the use of small quantities of reagents, increased safety parameters, and ready scale-up of synthetic procedures. A wide range of single and multiphase reactions has been performed in microfluidic-based devices. Certainly, microreactors cannot be applied to all chemistries yet and microfluidic systems also have disadvantages. Limited reaction time ranges, high sensitivity to precipitating products, and analytical challenges have to be overcome. An overview of microfluidic devices available for chemical synthesis is provided and some specific examples, mainly from our laboratory, are discussed to illustrate the potential of microreactors.

This article describes recent achievements of my research group in the Leibniz-Institut für Katalyse e.V. in the area of applied homogeneous catalysis for the synthesis of biologically active compounds. Special focus is given on the development of novel and practical palladium and copper catalysts for the functionalization of haloarenes and haloheteroarenes.

The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands.