1,720,970 research outputs found
Novel target in staphylococcus aureus
No full textStaphylococcus aureus (S. aureus), a representative opportunistic pathogen, catabolizes mannitol using mannitol 1-phosphatede hydrogenase (M1PDH) that mediates the NAD(P)/NAD(P)H dependent reversible conversion of mannitol 1-phosphate to fructose 6-phosphate. M1PDH is indispensable for the survival of S. aureus under stress environment, and can be a potential target for antibiotics to combat infectious diseases caused by this pathogen. Therefore, studies of structure and reaction mechanism of M1PDH are expected to not only uncover its role in bacterial energy metabolism, but also facilitate the structure-based design of inhibitors for the development of new antibiotics. We solved the crystal structure of S. aureus M1PDH at 1.8Å resolution, and identified essential residues for the recognition of mannitol and phosphate moieties. In addition, we have discovered that the catalytic direction of mannitol 1-phosphate/fructose 6-phosphate by M1PDH potentially depends on the solute concentration in the environment, which might provide a clue to the mechanism of how M1PDH regulates osmotic stress response in this pathogen. Furthermore, we identified the virulent effect of M1PDH during infection and introduced a novel strategy to eliminate clinical methicillin resistant S. aureus on the understanding of reverting the mannitol-osmotic regulation. Our study provides the molecular basis for the substrate selectivity of M1PDH and a new opportunity for the development of antibiotics against S. aureus infectio
The reactions of cyclotriphosphazene with 2-(2-hydroxyethylamino)ethanol. Spectroscopic studies of the derived products
No full textThe reactions of cyclotriphosphazene (1) with 2-(2-hydroxyethylamino)-ethanol (2) were investigated. 2-(2-hydroxyethylamino)-ethanol (2) is a tri-functional reagent consisting of both aliphatic hydroxyl and the secondary amino groups and its nucleophilic substitution reactions with cylotriphosphazene can lead to different product types; open chain, spiro, ansa, bridged and their mixtures. The reactions with one, two and three equimolar ratios of 2-(2-hydroxyethylamino)-ethanol, in the presence of NaH at 0–10 °C and at room temperature gave the following cyclotriphosphazene derivatives: one mono-spiro, N3P3Cl4[O–(CH2)2–NH–(CH2)2–O] (3, 1:1, r.t.); its isomer mono-ansa (5, 1:1, r.t.); one dispiro, N3P3Cl2[O–(CH2)2–NH–(CH2)2–O]2 (4, 1:1, r.t.); its isomer spiro-ansa (6, 1:2, r.t.); and one single-bridged compound with spiro substituted units, N3P3Cl3[O–(CH2)2–NH–(CH2)2–O]3N3P3Cl3 (7, 1:3, at 0–10 °C); as well as single-, N3P3Cl5[O–(CH2)2–NH–(CH2)2–O]N3P3Cl5 (8, 1:2, r.t.), double-, N3P3Cl4[O–(CH2)2–NH–(CH2)2–O]2N3P3Cl4 (9, 1:2, r.t.), and tri-bridged, N3P3Cl3[O–(CH2)2–NH–(CH2)2–O]3N3P3Cl3 (10, 1:3, at 0–10 °C) derivatives. Triple-bridged derivative is the major product in this system. The structures of the novel-derived compounds were characterized by TLC-MS, FT-IR, elemental analysis, 1H, and 31P NMR spectral.</p
PTSA-catalyzed reaction of alkyl/aryl methyl ketones with aliphatic alcohols in the presence of selenium dioxide: A protocol for the generation of an α-ketoacetals library
No full textA novel approach has been developed for the synthesis of a wide range of α-ketoacetals by the reaction of alkyl/aryl methyl ketones and aliphatic alcohols in the presence of selenium dioxide catalyzed by p-toluenesufonic acid. This method represents a general route to obtain a wide variety of α-ketoacetals in a simple, rapid, and practical manner. This approach is particularly attractive because of the easy availability of the starting materials, mild reaction temperature, and good yields of the products. The resulting α-ketoacetals are of much synthetic value as organic intermediates.</p
Flexible stereoselektive Funktionalisierung von Ketonen durch Umpolung mit hypervalenten Iodreagentien
No full textDie Funktionalisierung von Carbonylverbindungen in der α-Position hat aufgrund der biologischen Bedeutung der Produkte große Aufmerksamkeit als Syntheseweg erhalten. Durch Polaritätsumkehr (“Umpolung”) zeigen wir, dass Sauerstoff-, Stickstoff- und sogar Kohlenstoffnukleophile nach Anknüpfung an Enolether in Additionsreaktionen eingesetzt werden können. Unsere Resultate eröffnen die Möglichkeit neuer Retrosynthesen und einer raschen Erzeugung von vorher nur in vielstufigen Synthesen zugänglichen Strukturen
Suppression of the ubiquitin pathway by small molecule binding to ubiquitin enhances doxorubicin sensitivity of the cancer cells
No full textDevelopment of inhibitors for ubiquitin pathway has been suggested as a promising strategy to treat several types of cancers, which has been showcased by recent success of a series of novel anticancer drugs based on inhibition of ubiquitin pathways. Although the druggability of enzymes in ubiquitin pathways has been demonstrated, ubiquitin itself, the main agent of the pathway, has not been targeted. Whereas conventional enzyme inhibitors are used to silence the ubiquitination or reverse it, they cannot disrupt the binding activity of ubiquitin. Herein, we report that the scaffolds of sulfonated aryl diazo compounds, particularly Congo red, could disrupt the binding activity of ubiquitin, resulting in the activity equivalent to inhibition of ubiquitination. NMR mapping assay demonstrated that the chemical directly binds to the recognition site for ubiquitin processing enzymes on the surface of ubiquitin, and thereby blocks the binding of ubiquitin to its cognate receptors. As a proof of concept for the druggability of the ubiquitin molecule, we demonstrated that Congo red acted as an intracellular inhibitor of ubiquitin recognition and binding, which led to inhibition of ubiquitination, and thereby, could be used as a sensitizer for conventional anticancer drugs, doxorubicin
Iodoaminations of alkenes
Get PDFThe activation of alkenes and their subsequent functionalization is a frequently used methodology in synthetic chemistry. This review highlights recent iodine-mediated aminations and elaborates on the various strategies to bring about regio- or stereoselective transformations
Total synthesis of xanthoangelol B and its various fragments: towards inhibition of virulence factor production of Staphylococcus aureus
Get PDFAs an alternative strategy to fight antibiotic resistance, two-component systems (TCSs) have emerged as novel targets. Among TCSs, master virulence regulators that control the expression of multiple virulence factors are considered as excellent anti-virulence targets. In Staphylococcus aureus, virulence factor expression is tightly regulated by a few master regulators, including the SaeRS TCS. In this study, we used a SaeRS GFP-reporter system to screen natural compound inhibitors of SaeRS, and identified xanthoangelol B 1, a prenylated chalcone from Angelica keiskei as a hit. We have synthesized 1 and its derivative PM-56, and shown that 1 and PM-56 both had excellent inhibitory potency against the SaeRS TCS, as demonstrated by various in vitro and in vivo experiments. As a mode of action, 1 and PM-56 were shown to bind directly to SaeS and inhibit its histidine kinase activity, which suggests a possibility of a broad spectrum inhibitor of histidine kinases.</p
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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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