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Progettazione, sintesi e studio di inibitori multichinasici
Full text linkIn the field of cancer therapy, a primary role is played by ATP-competitive protein kinase inhibitors. Indeed, several drugs belonging to this class have been approved for therapy or are in advanced clinical trials1.
In the last years, the scientific research has been oriented towards the identification of multi-kinase inhibitors with controlled selectivity profile2.
The basis of this approach leans on the identification of exhaustive and effective structure-activity relationships.
In this work the design and the synthesis of 4 classes of 4-anilinopyrimidine derivatives as potential protein kinase inhibitors is discussed. These molecules present features useful for the identification of a complete pattern of structure-activity relationships.
The general structure of the designed compounds is reported in Figure 1.
4-anilino-6-phenylpyrimidine derivatives
4-anilino-6-phenylaminopyrimidine derivatives
4-anilino-5-phenylpyrimidine derivatives
4-anilino-5-phenylaminopyrimidine derivatives
Figure 1. General structure for the 4 classes of designed compounds.
The synthesis has been accomplished for almost all the compounds of the first 3 classes, while an effective synthetic strategy for 4-anilino-5-phenylamino-pyrimidine derivatives has not been identified yet.
Some of the synthesized compounds have been assayed against a panel of 48 kinases, in order to test their binding properties. All the data have been worked out and some preliminary SARs have been drawn. The same compounds have been assayed for their cytotoxicity against two tumoral cell linesNell’ambito della terapia antitumorale un ruolo di primaria importanza è rivestito dagli inibitori di proteinchinasi ATP-competitivi. Numerosi sono infatti i farmaci appartenenti a questa categoria attualmente in terapia o in avanzata sperimentazione clinica1.
La ricerca scientifica in questo settore si è negli ultimi anni orientata verso l’individuazione di inibitori multichinasici a selettività controllata2.
La base per una progettazione razionale di farmaci di questo tipo sta nell’individuazione di un profilo di relazioni struttura-attività efficace ed esaustivo.
In questo lavoro è discussa la progettazione e la sintesi di 4 classi di composti 4-anilinopirimidinici disegnati come potenziali inibitori di proteinchinasi, con caratteristiche tali da poter portare all’individuazione di un pattern di relazioni struttura-attività il più possibile completo. La struttura generale dei composti progettati è riportata in Figura 1.
Derivati 4-anilino-6-fenilpirimidinici
Derivati 4-anilino-6-fenilamminopirimidinici
Derivati 4-anilino-5-fenilpirimidinici
Derivati 4-anilino-5-fenilamminopirimidinici
Figura 1. Struttura generale delle 4 classi di composti progettate.
La sintesi è stata completata per quasi tutti i composti appartenenti alle prime tre classi, mentre non è stato possibile individuare una strategia sintetica efficace per i derivati 4-anilino-5-fenilamminopirimidinici.
Alcuni dei composti sintetizzati sono stati sottoposti a saggi enzimatici di binding nei confronti di un pannello di 48 chinasi. I dati ottenuti sono stati elaborati e sono state ricavate preliminari relazioni struttura-attività. Sugli stessi composti sottoposti a screening sono stati poi eseguiti saggi di citotossicità nei confronti di due linee cellulari tumoral
Libri e cultura a Ferrara nel secondo Cinquecento: la biblioteca privata di Alessandro Sardi. Seconda parte
No full textSeconda parte del contributo sulla biblioteca dell'erudito ferrarese Alessandro Sardi e i suoi libr
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
Discovery of Novel Quinazolinone Based mTOR Inhibitors Endowed with Antifibrotic Properties
No full textIn tissues after a prolonged injury or a chronic inflammation the persistence of repair processes leads to the aberrant extracellular matrix (ECM) deposition (i.e. tissue fibrosis). Fibrosis ultimately compromise the function(s) of the organ resulting in diseases (i.e. idiopathic pulmonary fibrosis, liver cirrhosis, or renal fibrosis, etc) responsible of several thousands of deaths per year. The massive ECM deposition is mediated by excessive/persistent release of pro-inflammatory cytokines and growth factors that stimulates myofibroblasts expansion, de-regulates metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression. To date the pharmacological care in patients with tissue fibrosis relies on corticosteroids and immunosuppressant drugs and it is rather unsatisfactory since often the ultimate resource is an organ transplant. Modern pharmacological strategies aim to take inhibiting specific components of the fibrogenic pathways by mean of monoclonal antibodies or small molecules.
Along this line, mTOR, a serine/threonine kinase belonging to the family of phosphoinositide 3-kinase related kinases, has emerged as a potential target for anti-fibrotic therapies.
Herein we report the discovery of novel quinazolinone based mTOR inhibitors that showed interesting antifibrotic properties while not showing cytotoxic activities.
The title compounds have been identified starting from the screening of an in-house library of properly designed potential kinase inhibitors. Those compounds that showed to be selective mTOR inhibitors have been then submitted to cytotoxic experiments. The molecules unable to impair cell viability have been then submitted to specific assays in order to investigate the antifibrotic properties. In particular, the selected molecules (at 1 μM) reduced the fibrosis-related mRNA transcript levels (i.e. collagen type I and fibronectin) in primary human hepatic stellate cells and intestinal myofibroblasts, two different cellular populations involved in the fibrogenic process of liver and gut, respectively.
Finally, molecular modelling studies (based on an homology model of mTOR kinase) have been used to propose a plausible binding mode for quinazolinone compounds
Autogrid-based clusterization of kinases: selection of representative conformations for docking purposes
No full textThe selection of the most appropriate protein conformation is a crucial aspect in molecular docking experiments.
In order to reduce the errors arising from the use of a single protein conformation, several authors suggest the use of several tridimensional structures for the target. However,
the selection of the most appropriate protein conformations
still remains a challenging goal. The protein 3D-structures
selection is mainly performed based on pairwise root-meansquare-deviation (RMSD) values computation, followed by hierarchical clustering. Herein we report an alternative strategy, based on the computation of only two atom affinity map for each protein conformation, followed by multivariate analysis and hierarchical clustering. This methodology was applied on seven different kinases of pharmaceutical interest.
The comparison with the classical RMSD-based strategywas
based on cross-docking of co-crystallized ligands. In the case
of epidermal growth factor receptor kinase, also the docking
performance on 220 known ligands were evaluated, followed
by 3D-QSAR studies. In all the cases, the herein proposed
methodology outperformed the RMSD-based one
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
Psoralen derivatives as NF-kB/DNA interaction inhibitors: structural insight into the binding mode
No full textNF-kB is a transcription factor involved in the control of a large number of normal cellular and organism processes, such as immune and inflammatory responses, cellular growth and apoptosis. The dysregulation of NF-kB is associated with many disease states such as AIDS and viral infections, arthritis and inflammatory diseases, cancer and also genetic disorders. In this way, targeting NF-kB could be of great interest in order to find new therapeutic agents, mainly anticancer and/or antiinflammatory compounds.
Recently, psoralen derivatives able to inhibit NF-kB/DNA interactions and the related IL-8 gene expression were identified.
Several novel psoralenes have been synthesized and evaluated through EMSA assay, in order to establish a Structure-Activity Relationship and to determine the structural determinant required to inhibit the NF-kB/DNA interaction.
The binding mode of the compounds has been determined combining docking and 3D-QSAR studies: initially, 4 putative interaction sites have been identified through molecular docking approach.
Then, the most plausible binding site has been selected by means of 3D-QSAR models
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