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Towards the discovery of novel sigma receptor modulators: organolithium-methods based synthesis and biological evaluations
No full textMein dreijähriges Projekt fokussierte sich auf zwei Hauptthemen, Sigmarezeptoren (SRs) und Lithiumcarbenoide, welche in den anschließenden Absätzen kurz zusammengefasst werden.
1.Sigmarezeptor Modulatoren als neuartige Targets in der Krebsbehandlung.
Die Motivation hinter meinem Projekt war die Notwendigkeit, neue „druggable“ Proteine als Targets zur Behandlung von Krebserkrankungen aufzufinden. Auf der Suche nach neuartigen krebsbekämpfenden Wirkstoffen, welche unter geringen Nebenwirkungen ihre Wirkung entfalten, sind SRs Modulatoren geeignet. Sigmarezeptoren sind in einer Vielzahl an physiologischen Funktionen involviert, unter anderem Lern- und Erinnerungsprozesse, Depressionen und Angstzustände, Schizophrenie, Analgesie und Krebs. Es gibt dabei zwei Unterarten von Sigmarezeptoren: S1R und S2R, basierend auf anatomischer Verteilung sowie pharmakologischer und pathologischer Aktivitäten. S1Rs sind gut bekannt und bisher wurden mehrere Modulatoren entdeckt. Insbesondere wurde für S1R-Agonisten gezeigt, dass sie neuroprotektive und neuroplastische Effekte haben, wohingegen S1R-Antagonisten zu positiven Wirkungen gegen neuropathischen Schmerzen und Krebs führen. Im Gegensatz dazu ist S2R immer noch nicht hinreichend bekannt, sowohl in struktureller als auch in pharmakologischer Hinsicht. Zahlreiche experimentelle Ergebnisse zeigen aber eine Überausscheidung dieses Targets in Krebszellen und die Wissenschaft unterstützt die Idee, dass S2R-Modulatoren antiproliferative und proapoptotische Effekte haben könnte. Damit einhergehend verwenden wir einigen Aufwand dafür, Antikrebs-Wirkstoffe zu finden, die via SR-Modulation wirken. Genau gesagt haben wir ein QSAR-Modell erstellt, basierend auf in der Literatur veröffentlichter Daten und Daten aus unserer hauseigenen Bibliothek. Dieser Ansatz hat es erlaubt, die strukturellen Eigenschaften zu identifizieren, die eine hohe Affinität gegenüber beiden SR-Subtypen garantieren. Aus dieser Studie ging hervor, dass Verbindungen mit sperrigen Amin-Gruppen, z.B. 4-Benzylpiperidin, pan-SR affin sind. Daher entwarfen und synthetisierten wir eine Reihe an razemischen und enantiomeren Arylalkyl(alkenyl)-4-Benzylpiperidin-Derivaten. Auf Grund des Bindungscharakters bezüglich S1R und S2R, sowie den cytotoxischen Eigenschaften einer Menge an Krebszelllinien, wählten wir RC-106 als den vielversprechendsten antiproliferativen Wirkstoff. Wir glauben, dass RC-106 ein vielversprechender Kandidat für einen Antikrebs-Wirkstoff ist, weitergehende Untersuchungen dieser Eigenschaften sind im Gange. Zu guter Letzt wurde ein Biotin-Pan-SR-Konjugat als pharmakologisches Werkzeug entworfen, das dazu fähig ist, die Aufnahme an antiproliferativen Molekülen in Krebszellen zu erhöhen und Nebenwirkungen zu vermeiden. Trotz widerholten Versuchen wurde nicht das gewünschte Produkt gefunden.
2. Lithiumcarbenoide, nützliche homologierende Stoffe
Während eines Aufenthaltes an der Universität Wien wurden die Reaktivität und Stabilität der Lithiumcarbenoide gegenüber Enonsubstraten untersucht. Das Hauptziel dieser Untersuchung war die Anwendbarkeit dieser Reagenzien gegenüber Ketonderivaten des RC-106 zu verifizieren, um das Hauptzwischenprodukt für spätere Funktionalisierung zu gewinnen. Die Einführung einer Methylen-Gruppe in der Wirkstoffstruktur kann zu einer Modifikation ihrer pharmakologischen Eigenschaften führen, somit stellen Homologisierungsreaktionen wichtige Synthese-Schritte dar, welche dem Auffinden bioaktiver Verbindungen dienen. Vor allem carbenoidgesteuerte Homologierungen sind wertvolle Alternativen zu den manchmal gefährlichen C-C Reaktionen. Carbenoide sind von der Gegenwart elektronenspendender und elektronenziehender Substituenten charakterisiert, diese Elemente geben dem Kohlenstoffzentrum eine ambiphile Aktivität. So können Carbenoide abhängig von den experimentellen Bedingungen als Elektrophile und Nukleophile agieren, was ihrer Vielfältigkeit gegenüber unterschiedlicher Substrate zuzurechnen ist. Sie werden als bedeutende Reaktanden der Organischen Chemie gesehen. Die dabei ausgeübte Tätigkeit ist Teil dieses Szenarios und eine Fortsetzung der vorangehenden Publikationen von Pace et al., welche Strategien zu einer chemoselektiven 1,2-Addition von LiCH2Cl zu zyklischen Enonen entwickelten. Sobald die Anwendbarkeit dieser Lithiumcarbenoide gegenüber diesen Ketonen bestätigt wurde, konnten Reaktivität und Stabilität dieser Spezies weiter untersucht werden. Somit richtete sich der Fokus auf die Untersuchung der Parameter mit einem Spritzpumpen-Apparat, welcher das Verhalten von Monohalomethyllithium-Reagenzien beeinflussen könnte. Unerwartete Produkte wurden dabei erhalten. Tatsächlich kann unter besonderen Bedingungen eine doppelte Homologisierung stattfinden, bei welcher Aldehyde angefügt wurden. Die unerwartete Reaktion wurde untersucht und der grundlegende Mechanismus dahinter gefunden.My three-years-project has been focused on two main topics, Sigma Receptors (SRs) and Lithium carbenoids, as briefly summarized in the following paragraphs.
1. Sigma Receptors as novel targets for the cancer treatment.
The driving force of my project work has been the need of finding “druggable” proteins as new molecular targets to treat cancer conditions. In the discovery of novel anticancer agents, able to guarantee a result with poor side effects, SRs modulators are fit for purpose. Briefly, Sigma Receptors are involved in a large number of physiological functions including learning and memory processes, depression and anxiety, schizophrenia, analgesia and cancer. There are two subtypes of Sigma Receptors: S1R and S2R based on anatomical distribution, pharmacological and pathological activities. S1Rs are well known and several modulators have been identified so far. Particularly, S1R agonists are proved to exert neuroprotective and neuroplastic effects whereas S1R antagonists give rise to beneficial activities against neuropathic pain and cancer. Conversely, S2Rs still present enigmatic aspects, both from structural and pharmacological point of view. However, numerous experimental evidences show the overexpression of this molecular target in cancer cells and the scientific community strongly supports the idea that S2R modulators may have antiproliferative and proapoptotic effects. Accordingly, we spent some of our efforts in identifying new anticancer agents, acting via SR modulation. In detail, we generated a QSAR model, using the activity data published in literature and our in-house library. This approach allowed to identify the structural features that guarantee a high affinity towards both SR subtypes. From this study emerged that compounds presenting a bulky aminic portion, i.e. 4-benzylpiperidine, possess pan-SR affinity. Therefore, we designed and synthetized a compound series of racemic and enantiomeric arylalkyl(alkenyl)-4-benzylpiperidine derivatives. On the bases of binding profile towards S1R and S2R and of its cytotoxic properties towards a panel of cancer cell lines, we select RC-106 as the most promising antiproliferative agent. We believe that RC-106 may be considered a valuable anticancer candidate and an in depth investigation of its anticancer properties is in progress. Lastly, a biotin-pan-SR conjugate has been designed as pharmacological tool able to enhance the uptake of antiproliferative molecules in cancer cells, as well as to avoid side effects. Although several attempts have been carried out, up to now, the desired product has not been obtained.
2. Lithium carbenoids, useful homologating agents.
During my experience at the University of Vienna, I studied the reactivity/stability of lithiumcarbenoids toward enone substrates. The final aim of this study was to verify the applicability of these reagents towards ketone derivatives of RC-106, in order to obtain key intermediate for future functionalization. The introduction of methylene groups in the drug structure may lead to a modification of its pharmacological properties and therefore homologation reactions represent important synthetic steps useful to obtain bio- active compounds. Particularly, carbenoid-mediated homologations are valuable alternative to the traditional and sometimes hazardous C-C reactions. Carbenoids are characterized by the presence of an electron-donating and an electron-withdrawing substituent, these elements confer to the carbon center an ambiphilic activity. Carbenoids may act as nucleophiles or as electrophiles, depending on the experimental conditions and, thanks to their versatility towards different substrates, they are considered important reagents in organic chemistry. The work presents herein is part of this scenario and it is a pursuance of the prior publication of Pace and co-workers, which developed a strategy to carry out a chemoselective 1,2-addition of LiCH2Cl to cyclic enones. Once the applicability of the lithium carbenoids towards these ketones has been confirmed, the reactivity/stability of these species has been investigated in depth. Therefore, we focused on the study of the parameters that may influence the behavior of monohalomethyllithium reagents, using a syringe pump instrument. Interestingly, from this work unexpected products emerged. Indeed, under particular conditions, a double homologation may occur, furnishing aldehydes. We analyzed this surprising reaction and disclosed the mechanism that took place
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
New perspectives in cancer therapy: the biotin-antitumor molecule conjugates
No full textChemotherapy is still the first-line treatment of cancer, even if drugs currently used in therapy generally possess high toxicity and poor selectivity. In the last two decades several efforts have been made to overcome these drawbacks by specifically carrying anticancer drugs to the tumors. Among the different approaches, the so called vitaminmediated drug targeting has recently emerged as a novel and valuable strategy. Indeed, the linkage of cytotoxic drugs to selected vitamins, leading to vitamin-drug conjugates, would result in specifically delivering great amounts of the targeted drug at high doses to cancer cells. Among vitamins, biotin seems to be the most promising targeting agent.
The aim of this review is to get an overview on recent success in the conjugation of biotin with molecules endowed with anticancer properties
New Perspectives in Lithium Carbenoid Mediated Homologations
No full textα-Functionalized organolithium reagents (e.g. LiCH2X) are versatile reagents for accomplishing homologations of carbon- and heteroatom-type electrophiles. The proper selection of the reaction conditions allows one to direct their intrinsic ambiphilicity towards the nucleophilic character. Herein, the homologation of various electrophiles ranging from Weinreb amides to isocyanates, carbonyl derivatives and chalcogenides – with a particular focus on the chemoselectivity of the processes - is contextualize
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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