1,720,987 research outputs found
Sugar-modified nucleosides: synthesis, conformational analysis and biological evaluation
No full textNucleoside analogues are a pharmacologically diverse family that includes cytotoxic compounds, antiviral agents and immunosuppressive molecules. Considerable progress has been made in the search for novel nucleoside structures with anticancer and/or antiviral activity by modifications in the nucleobase and/or in the sugar moiety and several branched-chain sugar nucleosides have shown potent antitumor activity. These agents behave as antimetabolites that interact with a number of intracellular targets blocking the DNA chain elongation or interfering with biosynthesis of nucleosides and nucleotides, a limiting process in cell proliferation. Many of the enzymes involved in these pathways are highly active in cancer cells, such as ribonucleotide reductase (RNR). RNR is a multisubunit radical-containing enzyme involved in the conversion of ribonucleoside diphosphates to the corresponding 2'-deoxyribonucleotides, which are building blocks for DNA replication and repair. Increased RNR activity has been associated with malignant transformation and tumor cell growth; it is therefore an excellent target for cancer chemotherapy. In recent years, several nucleoside RNR inhibitors have entered clinical trial or application such as arabinosylcytosine (ara-C), gemcitabine, cladribine, fludarabine and clofarabine. A previous structure-activity relationship study reported by us, identified the 3'-C-methyladenosine (3'-Me-Ado) as a mechanism-based RNR inhibitor endowed with a significant antitumor activity against a panel of human leukemia and carcinoma cell lines. To further investigate the structural determinants of 3'-Me-Ado required for the antitumor activity, in the first part of my PhD project, a number of 3'-C-methyl ribonucleosides with different purinic and pyrimidinic nucleobases and the 3'-C-methyl derivatives of the antitumor agents 5-fluorouridine and 9-( Î2-D-arabinofuranosyl)- adenine were synthesized and evaluated on human tumor cell lines. The biological results showed that the structure of 3'-Me-Ado is crucial for the antitumor activity of this type of ribose-modified nucleosides. A further structure-activity relationship study of synthesized adenine 3'-C-methylribonucleosides containing different substituent at N6-amino group of nucleobase such as a cycloalkyl, aryl or heteroaryl group confirmed that any modification in the structure of 3'-Me-Ado is detrimental for the antitumor activity. The obtained results have been rationalized by docking studies utilizing the X-ray structure of the subunit Rnr1 of the RNR from Saccharomyces cerevisiae complexed with ADP. The ribose recognition domain of adenosine derivatives appears to be of considerable importance not only for cytotoxic activity, but also for agonistic activity at adenosine receptors (ARs). The physiological agonist adenosine modulates a variety of functions through four receptor subtypes classified as A1, A2A, A2B and A3. A1 adenosine receptors (A1 ARs) are expressed in high density in the brain, in adipose tissue and in medium to low levels in many peripheral organ and tissues such as heart, lung and kidney. Thus, A1 agonists have many therapeutic potentials; however the clinical application of A1 full agonists is hampered by several side effects. In this respect, it has been reported that A1 partial agonist may be therapeutically advantageous. Among the adenosine derivatives, some 5'-chloro-5'-deoxy-N6-cycloalkyl(bicycloalkyl)- analogues were found A1 agonists with high affinity and selectivity for rat A1 AR or partial agonists for this AR subtype. In the search for potent and selective A1 AR agonists we have previously investigated a series of 2'-C-methylribofuranosyl analogues of selective A1 AR agonists and 2-chloro- 2'-C-methyl-N6-cyclopentyl-adenosine (2'-Me-CCPA) emerged as a potent and highly selective full agonist at rat, bovine and human A1 vs A2A, A2B and A3 ARs. On the base of these findings, in the second part of my work, a series of 5'-substituted derivatives of potent and selective A1 AR agonists were synthesized and tested for affinity and selectivity at different model of adenosine receptor subtypes. In particular, a series of 5'-carbamoyl or 5'-thionocarbamoyl derivatives of 2'-Me-CPA, 2'-Me-CCPA, N6-[(R)-3-tetrahydrofuranyl]adenosine and 2-chloro analogue were synthesized and evaluated for binding affinity at ARs from bovine, porcine and human species. Moreover, a series of 5'-chloro-5'-deoxy-N6-cycloalkyl(bicycloalkyl)-substituted adenosine and 2'-C-methyladenosine derivatives and 2-chloro analogues were synthesized and evaluated for affinity and efficacy at all cloned human AR subtypes. In this study, two adenosine derivatives displayed the highest affinity in the subnanomolar range and relevant selectivity for hA1 vs the other human receptor subtypes. This result was rationalized by a molecular modeling analysis
Synthesis and antitumor activity of a heterodinucleotide of BVDU and Gemcitabine
No full textA heterodinucleotide comprising BVDU and Gemcitabine bound together by a 5',5'-pyrophospate bridge (BVDUp(2)dFdC) has been synthesized and evaluated as antitumor agent against AH13 rat sarcoma cells. BVDUp(2)dFdC showed a cytotoxicity similar to that of Gemcitabine
First TiCl4-Mediated Diastereoslective Reduction of alpha-Nitro Ketones to beta-Nitro Alcohols by BH3.SMe2
No full textThe paper shows the efficient conditions for the reduction of R-nitro ketones to give the corresponding nitro alcohols. In some cases the diastereoselectivity was very good (>90:10 anti/syn). The presence of the Lewis acid was found to be pivotal in determining the stereo- chemical outcome of these reactions. Strongly chelating TiCl4 led largely to the anti diastereomer with BH3‚SMe2 as reducing agent
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
Purine and pyrimidine nucleoside analogs of 3'-C-methyladenosine as antitumor agents
No full text3′-C-Methyladenosine (3′-Me-Ado) is a mechanism-based ribonucleotide reductase inhibitor endowed with antitumor activity against both human leukemia and carcinoma cell lines. In this paper, we report the synthesis and antitumor evaluation of a series of purine and pyrimidine 3′-C-methylribonucleoside analogs of 3′-Me-Ado. A stereoselective synthesis of the arabino analog of 3′-Me-Ado is also described. Among the tested compounds, only 3′-C-methyluridine showed moderate antitumor activity against human myelogenous leukemia K562 cell lin
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