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News Article | May 23, 2017
Site: www.eurekalert.org

(Vienna, May 22, 2017) Two drugs taken together can sometimes lead to outcomes that largely deviate from the effect of the separated compounds - a fact well known from warnings on patient information leaflets. However, while doctors strongly advice against unsupervised mixing of drugs, the synergy of two combined pharmaceuticals assessed in an experimental setting can reveal completely new therapeutic options. Nevertheless, finding a novel combination of drugs for a given disease within the more than 30,000 drug products approved by the regulatory agencies was hitherto a big challenge for scientists. To facilitate systematic screening for synergistic interactions of drugs, CeMM PI Stefan Kubicek and his colleagues established a collection of 308 compounds (CeMM Library of Unique Drugs, CLOUD) that effectively represent the diversity of structures and molecular targets of all FDA-approved chemical entities. Moreover, the scientists proved the potential of the CLOUD with CeMM´s highly automated chemical screening platform by identifying a novel synergistic effect of two drugs (flutamide and phenprocoumon (PPC)) on prostate cancer cells. The results of Kubicek´s team with Marco Licciardello as first author were published in Nature Chemical Biology (DOI:10.1038/nchembio.2382) For the establishment of the CLOUD, a clever series of condensation steps was necessary: the CeMM scientists first determined and extracted 2171 unique active pharmaceutical ingredients from the database, discarding all products with identical compounds. Next, they removed large macromolecules like antibodies as well as salt fragments, and discarded all molecules that exert their biological effects through mechanisms other than protein-ligand interactions, are not used to treat diseases or are found only in topical products. With the remaining 954 systemically active small molecules (STEAM collection), the work had just begun: in order to create a comprehensive collection of compounds that fits on a standard 384-well screening plate, the researchers appended biological activities to all drugs with known molecular targets and grouped them into 176 classes of similar structure and activity. With a sophisticated clustering algorithm, 239 representative drugs were selected from those classes. Combined with 34 drugs with unknown target and 35 active forms of prodrugs (that otherwise need to be metabolized to become active), 308 compounds were selected in total for the CLOUD - the world´s first library representing all FDA-approved chemical entities including the active form of prodrugs. To put the combinatorial screen with the CLOUD to the test, Kubicek's group investigated the effect of pairwise combinations of CLOUD compounds on the viability on KBM7 leukemia cells, a cell line well suited for drug experiments. Using a dose chosen for each compound individually based on the clinically relevant maximum plasma concentration, the scientists found a strong synergistic interaction between flutamide, a drug approved for the treatment of prostate cancer, and phenprocoumon (PPC), an anti-thrombosis compound. In combination, flutamide and PPC efficiently killed the cancer cells. After identifying the androgen receptor (AR) as molecular target of the synergistic interaction, the scientists tried the drug combination on prostate cancer cells known to be hard to treat - and hit the bulls eye. "The combination induced massive cell death in prostate cancer cells. We then went back to the entire approved drug list, and indeed, we could show that all drugs from the clusters that flutamide and phenprocoumon represent synergize. Thereby we validated the reductionist concept underlying the CLOUD library," Stefan Kubicek explains. With their experiments, Kubicek´s team in collaboration with scientists from the Medical University of Vienna, the Uppsala University, Enamine Kiev and the Max Planck Institute for Informatics in Saarbrücken proved that the CLOUD is the ideal set of compounds to develop screening assays and discover new applications for approved active ingredients. At CeMM, a number of key discoveries on new applications for approved drugs have already been made with the CLOUD. Furthermore, as shown in the current issue of Nature Chemical Biology, the CLOUD is ideal for finding new drug combinations. "In view of these successes, I would predict that this set of compounds will become world standard for all screening campaigns", Stefan Kubicek emphasizes. Attached pictures: 1) Schematic representation of the filtering and clustering procedure leading to the 308 CLOUD drugs (© Nature Chemical Biology / Stefan Kubicek), 2) Immunofluorescence analysis of prostate cancer cells treated with 15mM flutamide, 35 μM PPC or the combination for 24 h. Scale Bar 20 μM (© Nature Chemical Biology / Stefan Kubicek) 3) Senior author Stefan Kubicek (© CeMM/Sazel) The study "A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor" was published online in advance in Nature Chemical Biology on May 22, 2017. DOI:10.1038/nchembio.2382 The study was funded by a Marie Curie Career Integration Grant, the Austrian Federal Ministry of Science, Research and Economy, the National Foundation for Research, Technology, and Development and the Austrian Science Fund (FWF). Stefan Kubicek studied organic chemistry in Vienna and Zürich. He received his Ph.D. in Thomas Jenuwein's group at the Institute for Molecular Pathology (IMP) in Vienna followed by postdoctoral work with Stuart Schreiber at the Broad Institute of Harvard and MIT in the U.S. He joined CeMM in 2010. He is the Head of the Chemical Screening at CeMM and the Platform Austria for Chemical Biology (PLACEBO) and the Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives. The mission of CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is to achieve maximum scientific innovation in molecular medicine to improve healthcare. At CeMM, an international and creative team of scientists and medical doctors pursues free-minded basic life science research in a large and vibrant hospital environment of outstanding medical tradition and practice. CeMM's research is based on post-genomic technologies and focuses on societally important diseases, such as immune disorders and infections, cancer and metabolic disorders. CeMM operates in a unique mode of super-cooperation, connecting biology with medicine, experiments with computation, discovery with translation, and science with society and the arts. The goal of CeMM is to pioneer the science that nurtures the precise, personalized, predictive and preventive medicine of the future. CeMM trains a modern blend of biomedical scientists and is located at the campus of the General Hospital and the Medical University of Vienna. http://www. For further information please contact Mag. Wolfgang Däuble Media Relations Manager CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria Phone +43-1/40160-70 057 Fax +43-1/40160-970 000 wdaeuble@cemm.oeaw.ac.at http://www.

Kappe C.O.,Christian Doppler Laboratory
Chemical Society Reviews | Year: 2013

High-speed microwave chemistry has attracted considerable attention in the past two decades with new and innovative applications in organic and peptide synthesis, polymer chemistry, material sciences, nanotechnology and biochemical processes continuously being reported in the literature. In particular the introduction of benchtop single-mode microwave reactors just over ten years ago has revolutionized the way many scientists today perform reactions in the laboratory. Unfortunately, the accurate measurement of reaction temperature in these devices is far from being trivial and requires both a basic understanding of microwave dielectric heating effects and use of appropriate temperature monitoring devices. In this tutorial review frequently occurring problems in the determination of accurate reaction temperatures in single-mode microwave reactors are discussed. © 2013 The Royal Society of Chemistry.

Schmidt-Erfurth U.,Christian Doppler Laboratory | Waldstein S.M.,Christian Doppler Laboratory
Progress in Retinal and Eye Research | Year: 2016

Neovascular age-related macular degeneration (AMD) has undergone substantial break-throughs in diagnostic as well as therapeutic respect, with optical coherence tomography (OCT) allowing to identify disease morphology in great detail, and intravitreal anti-vascular endothelial growth factor therapy providing unprecedented benefit. However, these two paths have yet not been combined in an optimal way, real-world outcomes are inferior to expectations, and disease management is largely inefficient in the real-world setting. This dilemma can be solved by identification of valid biomarkers relevant for visual function, disease activity and prognosis, which can provide solid guidance for therapeutic management on an individual level as well as on the population base.Qualitative and quantitative morphological features obtained by advanced OCT provide novel insight into exudative and degenerative stages of neovascular AMD. However, conclusions from structure/function correlations evolve differently from previous paradigms. While central retinal thickness was used as biomarker for guiding retreatment management in clinical trials and practice, fluid localization in different compartments offers superior prognostic value: Intraretinal cystoid fluid has a negative impact on visual acuity and is considered as degenerative when persisting through the initial therapeutic interval. Subretinal fluid is associated with superior visual benefit and a lower rate of progression towards geographic atrophy. Detachment of the retinal pigment epithelium was identified as most pathognomonic biomarker, often irresponsive to therapy and responsible for visual decline during a pro-re-nata regimen. Alterations of neurosensory tissue are usually associated with irreversible loss of functional elements and a negative prognosis. Novel OCT technologies offer crucial insight into corresponding changes at the level of the photoreceptor - retinal pigment epithelial - choriocapillary unit, identifying the biological limits of therapeutic interventions.To optimally benefit from high-resolution multi-modal imaging, an integrated analysis of all functional and structural features is required involving reliable automated algorithms and computational data analyses. Using innovative analysis methods, retinal biomarkers can be used to provide efficient personalized therapy for the individual patient, predictive disease- and population-based models for large-scale management and identifying promising targets for the development of novel therapeutic strategies. © 2015 Elsevier Ltd.

Cantillo D.,Christian Doppler Laboratory | Baghbanzadeh M.,Christian Doppler Laboratory | Kappe C.O.,Christian Doppler Laboratory
Angewandte Chemie - International Edition | Year: 2012

The best of both worlds: The benefits of homogeneous and heterogeneous nanocatalysis are combined, whereby highly reactive colloidal Fe 3O 4 nanocrystals are generated in situ that remain in solution long enough to allow the efficient and selective reduction of nitroarenes to anilines in continuous-flow mode (see scheme). After completion of the reaction, the nanoparticles aggregate and can be recovered by a magnet. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Wagner W.,Christian Doppler Laboratory
ISPRS Journal of Photogrammetry and Remote Sensing | Year: 2010

Small-footprint (0.2-2 m) airborne laser scanners are lidar instruments originally developed for topographic mapping. While the first airborne laser scanners only allowed determining the range from the sensor to the target, the latest sensor generation records the complete echo waveform. The waveform provides important information about the backscattering properties of the observed targets and may be useful for geophysical parameter retrieval and advanced geometric modelling. However, to fully utilise the potential of the waveform measurements in applications, it is necessary to perform a radiometric calibration. As there are not yet calibration standards, this paper reviews some basic physical concepts commonly used by the remote sensing community for modelling scattering and reflection processes. Based purely on theoretical arguments it is recommended to use the backscattering coefficient γ, which is the backscatter cross-section normalised relative to the laser footprint area, for the radiometric calibration of small-footprint full-waveform airborne laser scanners. The presented concepts are, with some limitations, also applicable to conventional airborne laser scanners that measure the range and intensity of multiple echoes. © International Society for Photogrammetry and Remote Sensing, Inc. (ISPRS).

Kappe C.O.,Christian Doppler Laboratory | Van Der Eycken E.,Catholic University of Leuven
Chemical Society Reviews | Year: 2010

First described almost a decade ago, "click" reactions such as the Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) are widely used today in organic and medicinal chemistry, in the polymer and material science field, and in chemical biology. While most click reactions can be performed at room temperature there are instances where some form of process intensification is required. In this tutorial review, aimed at the synthetic chemistry community, examples of click chemistry carried out under non-classical reaction conditions, such as for example applying microwave heating or continuous flow processing will be highlighted. © 2010 The Royal Society of Chemistry.

Moseley J.D.,Astrazeneca | Kappe C.O.,Christian Doppler Laboratory
Green Chemistry | Year: 2011

The question "why should microwave chemistry be green?" is evaluated in the context of the twelve principles of green chemistry, with a focus on the 6th principle: design for energy efficiency. A significant number of publications on microwave-assisted organic transformations during the past 25 years describe this non-classical heating technology as being "green", assuming that microwave dielectric heating is more energy efficient than classical conductive heat transfer methods. In this Perspective article, we critically assess the energy efficiency of microwave-assisted transformations in the context of scaling-up this technology to production quantities. © The Royal Society of Chemistry.

Kappe C.O.,Christian Doppler Laboratory
Angewandte Chemie - International Edition | Year: 2013

Selective heating or superheating? The enhancement effects seen by Dudley and co-workers in the microwave-heated Friedel-Crafts alkylation (see graphic) are due to superheating of the bulk reaction mixture and not selective reactant heating. This argument forms the basis of this Correspondence. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Kappe C.O.,Christian Doppler Laboratory
Accounts of Chemical Research | Year: 2013

In the past few years, the use of microwave energy toheat chemical reactions has become an increasingly popular theme in the scientific community. This nonclassical heating technique has slowly progressed from a laboratory curiosity to an established method commonly used both in academia and in industry. Because of its efficiency, microwave heating dramatically reduces reaction times (from days and hours to minutes and seconds) and improves product purities or material properties among other advantages. Since the early days of microwave chemistry, researchers have observed rate-accelerations and, in some cases, altered product distributions as compared with reactions carried out using classical oil-bath heating. As a result, researchers have speculated that so-called specific or nonthermal microwave effects could be responsible for these differences. Much of the debate has centered on the question of whether the electromagnetic field can exert a direct influence on a chemical transformation outside of the simple macroscopic change in bulk reaction temperature.In 2009, our group developed a relatively simple "trick" that allows us to rapidly evaluate whether an observed effect seen in a microwave-assisted reaction results from a purely thermal phenomenon, or involves specific or nonthermal microwave effects. We use a microwave reaction vessel made from silicon carbide (SiC) ceramic. Because of its high microwave absorptivity, the vessel shields its contents from the electromagnetic field. As a result, we can easily mimic a conventionally heated autoclave experiment inside a microwave reactor under carefully controlled reaction conditions. The switch from an almost microwave transparent glass (Pyrex) to a strongly microwave absorbing SiC reaction vial under otherwise identical reaction conditions (temperature profiles, pressure, stirring speed) then allows us to carefully evaluate the influence of the electromagnetic field on the particular chemical transformation.Over the past five years we have subjected a wide variety of chemical transformations, including organic reactions, preparations of inorganic nanoparticles, and the hydrolysis of proteins, to the "SiC test." In nearly all of the studied examples, we obtained identical results from reactions carried out in Pyrex vials and those carried out in SiC vials. The data obtained from these investigations confirm that in the overwhelming majority of cases a bulk temperature phenomenon drives the enhancements in microwave chemistry and that the electromagnetic field has no direct influence on the reaction pathway. © 2013 American Chemical Society.

Pieber B.,Christian Doppler Laboratory | Kappe C.O.,Christian Doppler Laboratory
Green Chemistry | Year: 2013

The use of high-temperature/pressure gas-liquid continuous flow conditions dramatically enhances the iron-catalyzed aerobic oxidation of 2-benzylpyridines to their corresponding ketones. Pressurized air serves as a readily available oxygen source and propylene carbonate as a green solvent in this radically intensified preparation of synthetically valuable 2-aroylpyridines. This journal is © 2013 The Royal Society of Chemistry.

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