1,721,186 research outputs found
Chemical behaviour and crystallographic characterization of ureido 1,2,5-oxadiazole derivatives, related to Stat3 inhibitors
No full textSTAT3 (Signal Transducer and Activator for Transcription 3) is a latent cytosolic protein that directly relates extracellular signals(e.g. growth factors, poly-peptide, cytokines etc.) from the membrane to the nucleus [1]. STAT3 is constitutively
activated by aberrant upstream tyrosine kinase activities in a broad spectrum of human solid and blood tumours. Since STAT3
inhibition leads to apoptosis in tumour cells but not in normal cells, it represents a promising target for cancer therapy [2].
In our research we focused on the discovery of new ureido oxadiazole derivatives related to AVS-2088 (lead compound), as
potential STAT3 inhibitors, with the aim to identify the essential structure-activity requirements for the development of novel
active compounds.
Our previous results [3] indicated that the presence of a phenyl moiety in position 4 of the oxadiazole ring was critical for the
interaction with the biological target, so we planned the synthesis of the styryl derivatives.
On these basis, we analyzed the X-Ray structures of the compounds having the general formula reported in Figure 2 and
structure-activity relationships were derived. The drop in activity of the derivatives with respect to the lead could be due to the
presence of the common flexible benzyl chain linked to the urea that disrupted the flat conformation of the entire molecule,
influencing its orientation and interaction at the receptor site.
The synthetic procedures applied for the preparation of the new derivatives as well as the results of the crystallographic studies
and their biological evaluation will be presented.[1] Yu, H.; Jove, R. The STATs of cancer-new molecular targets come of age. Nat. Rev. Cancer 2004, 4, 97-105.
[2] D. Masciocchi, A. Gelain, S. Villa, F. Meneghetti, D. Barlocco. Signal Transducer and Activator of Transcription 3 (STAT3): a
promising target for anticancer therapy. Future Med. Chem. 2011, 3, 567-597.
[3] Shin, D.-S.; Masciocchi, D.; Gelain, A.; Villa, S.; Barlocco, D.; Meneghetti, F.; Pedretti, A.; Han, Y.-M.; Han, D. C.; Han, M.
Y.; Kwon, B.-M.; Legnani, L.; Toma L. Synthesis, modeling, and crystallographic study of 3,4-disubstituted-1,2,5-oxadiazoles
and evaluation of their ability to decrease STAT3 activity. Med. Chem. Comm. 2010, 1, 156-164
Structural and Conformational Studies of 3-(6-Chloropyridazin-3-yl)-N,N-dimethylpiperazinium Iodide and 3-(6-Chloropyridazin-3-yl)-N,N-dimethylhomopiperazinium Iodide with Central Nicotinic Action
No full textThe structural characteristics of 3-(6-chloropyridazin-3-yl)-N,N-dimethylpiperazinium iodide (3c) and 3-(6-chloropyridazin-3-yl)-N,N-dimethylhomopiperazinium iodide (4c) have been investigated in order to understand their actions at the nAchR receptor. The results of the X-Ray molecular structures and of the conformational analysis have been compared with the structure of epibatidine that represents one of the most potent nicotinic agonist
Docking of 6-chloropyridazin-3-yl derivatives active on nicotinic acetylcholine receptors into molluscan Acetylcholine Binding Protein (AChBP)
No full textThe crystal structure of Acetylcholine Binding Protein (AChBP), homolog of the ligand binding domain of nAChR, has been used as model for computational investigations on the ligand-receptor interactions of derivatives of 6-chloropyridazine substituted at C3 with 3,8-diazabicyclo[3.2.1] octane, 2,5-diazabicyclo[2.2.1]heptane and with piperazine and homopiperazine, substituted or not at N4. The ligand-receptor complexes have been analyzed by docking techniques using the binding site of HEPES complexed with AChBP as template. The good relationship between the observed binding affinity and the calculated docking energy confirms that this model provides a good starting point for understanding the binding domain of neuronal nicotinic receptors. An analysis of the possible factors significant for the ligand recognition has evidenced, besides the cation-φ interaction, the distance between the chlorine atom of the pyridazinyl group and the carbonylic oxygen of Leu B112 as an important parameter in the modulation of the binding energy
Crystal and molecular structures of h3-propenyl and h3-2-methyl propenyl-bis(triphenylphosphine) platinum (II) perchlorates
No full textStructural and conformational studies on two diasteromeric dihydroisoxazolyl cyclopropane derivatives
No full textThe molecular structures of 2-(3'-bromo-4',5'-dihydroisoxazol-5'-yl)-1-tert-butoxycarbonylaminocyclo propanecarboxylic acid (±)-10a and 1-amino-2-(3'-hydroxy-4',5'-diydroisoxazol-5'-yl)cyclopropanecarboxylic acid (±)-11b were determined by single crystal X-ray diffraction method. The geometrical features and the intermolecular interactions of the two diastereoisomers have been compared evidencing a different conformation of the dihydroisoxazole ring: in (±)-10a is almost planar, while in (±)-11 adopts an envelope shape. Intermolecular hydrogen bonds of OH...O and NH...O type in (±)-10a determine the formation of a three-dimensional network, whereas in (±)-11b polimeric chains due to NH...O interactions are obtained. These compounds are key intermediates of conformationally constrained glutamic acid homologues and the opposite stereochemistry of C(3) leads to different pharmacophoric distances, important for the ligand-receptor interaction. The results of the X-ray molecular structures have been complemented by theoretical calculations
Special Issue: Frontiers in Antimicrobial Drug Discovery and Design
Full text linkSince the discovery of Penicillin, antibiotics have saved millions of lives every year.[...
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
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