1,721,067 research outputs found
Synthesis of dual action Smac/Zinc-Chelator conjugates as putative proapoptotic agents
No full textApoptosis, or programmed cell death, is a critical cell process in normal development and homeostasis of multicellular organisms. It is now recognized that dysfunction of the apoptosis machinery is a hallmark of cancer. Accordingly, targeting critical apoptosis regulators is an attractive approach for the development of new classes of therapies for the treatment of cancer and other human diseases.
The X-linked inhibitor of apoptosis protein (XIAP) is a member of IAP proteins that potently inhibit apoptosis[1]. XIAP contains three baculovirus IAP repeat (BIR) domains. The mechanism of action of XIAP entails its binding with initiator and effector caspases through its BIR domains. In cells, the anti-apoptotic function of XIAP is antagonized by Smac/DIABLO (second mitochondria-derived activator of caspases or direct IAP binding protein with low pI). Despite the rather complex structure of Smac, its short N-terminal AVPI sequence is sufficient to trigger the inactivation of anti-apoptotic XIAP[2]. Our research group has shown how small monomeric, AVPI-inspired Smac mimics can bind XIAP on its BIR3 domain with sub-micromolar potency[3,4]. Executioner caspase-3, -6 and -7 exist within the cytosol as inactive zymogens (procaspases) activated by limited proteolysis within their inter-domain linker, carried out by an initiator caspaseThe essential executioner caspase-3 is proteolytically activated by either caspase-8 or -9. Zinc ions co-localize with procaspase-3/caspase-3 and inhibit its enzymatic activity in the cell by direct interaction with an Asp-Asp-Asp (DDD) “safety catch” region[5]. Thus, in this work we coupled a zinc chelator moiety based on di(picolylamide)amine (DPA) and its N,N-bis(pyridin-2-ylmethyl)ethane-1,2-diamine (BPEN) derivative to pro-apoptotic Smac mimetics, synthesized starting from known intermediates 1 and 2.
Dual action Smac mimetic-zinc chelators 3 and 4 were prepared from compounds 1 and 2 as shown in Scheme 1 and characterized in vitro, using cell-free and cellular assays[6,7]. Their ability to bind XIAP BIR3 domain, to process pro-caspase-3 to caspase-3 and their cytotoxicity have been experimentally determined, and favorably compared with those of a potent Smac mimic compound, especially for the most potent, tribasic dual action compound 4. Furthermore, the Zinc affinity for both compounds was confirmed by fluorescence measurements.
References
1. Q. L. Deveraux, J. C. Reed. Genes & Dev. 1999, 13, 239-252
2. J. Chai, C. Du, J. W. Wu, S. Kyin, X. Wang, Y.Shi. Nature 2000, 406, 855-862
3. P. Seneci, A. Bianchi, C. Battaglia, L. Belvisi, M. Bolognesi, A. Caprini, F. Cossu, E. de Franco, M. de, D.
Delia, C. Drago, A. Khaled, D. Lecis, L. Manzoni, M. Marizzoni, E. Mastrangelo, M. Milani,I. Motto, E.
Moroni, D. Potenza, V. Rizzo, F. Servida, E. Turlizzi, M. Varrone, F. Vasile, C. Scolastico. Bioorg. Med.
Chem. 2009, 17, 5834–5856.
4. L. Manzoni, D. Arosio, L. Belvisi, A. Bracci, M. Colombo, D. Invernizzi, C. Scolastico. J. Org. Chem. 2005, 70,
4124-4132.
5. K. S. Putt, G. W. Chen, J. M. Pearson, J. S Sandhorst, M. S. Hoagland, J. Kwon, S. Hwang, H. Jin, M. I.
Churchwell, M. Cho, D. R. Doerge, W. G. Helferich, P. J. Hergenrother. Nat. Chem. Biol. 2006, 2, 543, 550
6. Z. Nikolovska-Coleska, R. Wang, X. Fang, H. Pan, Y. Tomita, P. Li, P.P. Roller, K. Krajewski, N.G. Saito, J.A.
Stuckey, S. Wang, Anal. Biochem. 2004, 332, 261-273.
7. Z. Nikolovska-Coleska, J.L. Meagher, S. Jiang, S.A. Kawamoto, W. Gao, H. Yi, D. Qin, P.P. Roller, J.A.
Stuckey, S. Wang, Anal. Biochem. 2008, 374, 87-98
II. Rivista di Filología romanza, diretta da L. Manzoni, E. Monaci, E. Stengel, I, 1
No full textM. P. II. Rivista di Filología romanza, diretta da L. Manzoni, E. Monaci, E. Stengel, I, 1. In: Romania, tome 2 n°5, 1873. pp. 140-141
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
Synthesis of 8,5-fused bicyclic lactam by stereo- and regioselective radical cyclization
No full textA conformationally restricted dipeptide mimetic was synthesized via a regio- and stereoselective radical cyclization of an α-N-acetyl acrylamide
Synthesis of Lewis A and Lewis X pentasaccharides based on N-trichloroethoxycarbonyl protection
No full textThexyldimethylsilyl 4,6-O-benzylidene-2-deoxy-2-trichloroethoxycarbonylamino-beta-D-glucopyranoside (4), having the 3-hydroxy group unprotected, is a versatile starting material for the synthesis of glucosamine containing oligosaccharides. Thus, reaction with galactosyl donor 5 or fucosyl donor 6 afforded the desired beta(1-3)- and alpha(1-3)-linked disaccharides 7 and 8, respectively, in high yields, Reductive opening of the benzylidene moieties in 7 and 8 gave access to the 4-hydroxy groups in 9 and 10. Ensuing fucosylation of 9 or galactosylation of 10 led to Lewis A (Le(a)) and Lewis X (Le(x)) trisaccharide building blocks 13 and 14, respectively. Their transformation into glycosyl donors 19 and 20 and subsequent reaction with 3b-O-unprotected lactose derivative 23 as acceptor furnished the Le(a)- and Le(x) pentasaccharide precursors 24 and 25. Exchange of the N-trichloroethoxycarbonyl group for an N-acetyl group and removal of the O-benzyl and O-acetyl protective groups afforded the desired Le(a)- and Lex-pentasaccharides 1 and 2
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
- …
