1,720,959 research outputs found
Synthesis and Chemical Optimization of New Melatonergic Ligands, including Multitarget Compounds
Full text linkComplex multifactorial pathologies, such as metabolic syndrome, psychiatric or degenerative central nervous system disorders, and cancer, are often caused by deregulation of multiple pathways, and cannot be effectively treated with a single-target modulation. Therefore, the use of multitarget compounds represents a more valid and effective strategy for these pathologies. Both melatonin and endocannabinoid are pleiotropic signaling system involved in all aspects of mammalian physiology and pathology, and for this reason they represents potential targets for the design and development of new therapeutic drugs.
In my thesis work, I focused my attention on the synthesis of a different series of melatoninergic ligands, including new multitarget compounds able to also modulate the endocannabinoid system.
The single enantiomers of (±)-UCM1014, a potent and selective MT2-receptor agonist, were obtained through an appropriate optical resolution strategy. Pharmacological experiments demonstrated that (R)-UCM1014 is the eutomer, with about 160-fold selectivity for the MT2 receptor and full agonist behaviour. The combination of molecular docking simulations and investigation of the conformational equilibria in solution by molecular dynamics simulations and NMR spectroscopy allowed us to rationalize the stereoselective behavior shown by the two enantiomers. New melatonergic fluorescent probes were synthetized, introducing on the C-4 position of MLT indole a formyl moiety (CHO) and a cyano (CN) group. The 4-CHO-MLT and the 4-CN-MLT gave the desired red-shifted absorption and emission spectra, but a diminished binding affinity for the two receptors was observed. The chemical optimization of UCM765, a MT2 partial agonist, lead to the synthesis of a new series of N-anilinoethylamide derivatives, characterized by improved water solubility and increased metabolically stability. Different elements were considered for the optimization of this important classes of melatonergic ligands, including the study of the size and the orientation of substituents of the aromatic scaffold as well as the introduction of more hydrophilic groups, enhancing the water solubility, or protecting metabolically liable positions while preserving the high binding affinity and selectivity toward the MT2 receptor. Finally, dual MLT agonists-MAGL (monoacylglycerol lipase) inhibitors with suitable physicochemical properties have been obtained by fusion of the pharmacophore elements required at the two targets. The new dual-acting compounds displayed good to moderate activity at the melatonergic and endocannabinoid systems. The most active compound, resulting from the combination of N-anilinoethylamide scaffold with the O-hexafluoroisopropanol carbamate, is characterized by a balanced activity at both targets, and is currently under investigation for neuroprotective and anti-inflammatory effects in vivo.Complex multifactorial pathologies, such as metabolic syndrome, psychiatric or degenerative central nervous system disorders, and cancer, are often caused by deregulation of multiple pathways, and cannot be effectively treated with a single-target modulation. Therefore, the use of multitarget compounds represents a more valid and effective strategy for these pathologies. Both melatonin and endocannabinoid are pleiotropic signaling system involved in all aspects of mammalian physiology and pathology, and for this reason they represents potential targets for the design and development of new therapeutic drugs.
In my thesis work, I focused my attention on the synthesis of a different series of melatoninergic ligands, including new multitarget compounds able to also modulate the endocannabinoid system.
The single enantiomers of (±)-UCM1014, a potent and selective MT2-receptor agonist, were obtained through an appropriate optical resolution strategy. Pharmacological experiments demonstrated that (R)-UCM1014 is the eutomer, with about 160-fold selectivity for the MT2 receptor and full agonist behaviour. The combination of molecular docking simulations and investigation of the conformational equilibria in solution by molecular dynamics simulations and NMR spectroscopy allowed us to rationalize the stereoselective behavior shown by the two enantiomers. New melatonergic fluorescent probes were synthetized, introducing on the C-4 position of MLT indole a formyl moiety (CHO) and a cyano (CN) group. The 4-CHO-MLT and the 4-CN-MLT gave the desired red-shifted absorption and emission spectra, but a diminished binding affinity for the two receptors was observed. The chemical optimization of UCM765, a MT2 partial agonist, lead to the synthesis of a new series of N-anilinoethylamide derivatives, characterized by improved water solubility and increased metabolically stability. Different elements were considered for the optimization of this important classes of melatonergic ligands, including the study of the size and the orientation of substituents of the aromatic scaffold as well as the introduction of more hydrophilic groups, enhancing the water solubility, or protecting metabolically liable positions while preserving the high binding affinity and selectivity toward the MT2 receptor. Finally, dual MLT agonists-MAGL (monoacylglycerol lipase) inhibitors with suitable physicochemical properties have been obtained by fusion of the pharmacophore elements required at the two targets. The new dual-acting compounds displayed good to moderate activity at the melatonergic and endocannabinoid systems. The most active compound, resulting from the combination of N-anilinoethylamide scaffold with the O-hexafluoroisopropanol carbamate, is characterized by a balanced activity at both targets, and is currently under investigation for neuroprotective and anti-inflammatory effects in vivo
General synthesis of unnatural 4-, 5-, 6-, and 7-bromo-d-tryptophans by means of a regioselective indole alkylation
No full textA general two-step approach to enantiopure bromotryptophans from unprotected bromoindoles has been developed. Indole nucleophiles prepared with MeMgCl in the presence of CuCl reacted with cyclic sulfamidates derived from enantiopure D-serine to form 4-, 5-, 6-, or 7-bromo-D-tryptophan and some other halogenated tryptophans in moderate yields but with complete regioselectivity. The bromotryptophan derivatives were deprotected using mild conditions
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
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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