1,720,966 research outputs found
Novel hydrazone derivatives having potent antitumor activity toward multi-drug resistant tumor cells
No full textA patentable new class of hydrazone derivative compounds is described, as are methods for synthesizing such compounds. The hydrazones of the invention can be used, for example, as potent anticancer agents, including to inhibit the growth of cancer cells that exhibit multidrug resistance
New N6-substituted adenosine and 3’-C-methyl-adenosine derivatives as antitumor agents
No full textMany analogues of the natural nucleosides modified at nucleobase or at sugar moiety have been developed on the basis of their therapeutic potential as antitumor antiviral and antiprotozoal agents. Among the N6-modified adenosine analogues, N6-hydroxy, N6-methoxy, and N6-amino derivatives have proved to be potent cytotoxic agents acting through letal mutagenesis. Moreover, modification at the ribose moiety of purine nucleosides resulted in potent antitumor agents, such as in the case of 3'-C-methyladenosine (3'-MeAdo), recently developed by us as a mechanism-based ribonucleotide reductase (RR) inhibitor, that displayed a significant cytotoxicity against a panel of human leukemia and carcinoma cell lines.1 We now report on the synthesis and antitumor activity of a series of 3'-C-methyladenosine derivatives substituted at N6 with a hydroxy, methoxy or amino group. Furthmore, azinyl hydrazone containing a N*-N*-N* structural motif able to inhibit RR were also prepared starting from N6-.amino-adenosine or N6-amino-3'-C-methyladensine. The stereochemistry of these compounds was established to be Z by means of NMR spectroscopy. The antiproliferative activity of the substituted purine nucleosides against a panel of human tumor cell lines will be presented.
1 (a) Franchetti P et al J Med Chem 2005, 48, 4983-89; (b) Cappellacci et al J Med Chem 2008, 51, 4260-6
Dual-target dimeric molecules with antitumor properties. Synthesis and biological activity of 3’-C-methyladenosine-valproates
No full textIn recent years, together with development of new antitumor drugs, significant efforts have been directed toward the development of combination therapies in the treatment of different types of cancers. Some enzymes that play vital roles in DNA replication and transcription, such as ribonucleotide reductase (RR) and histone deacetylases (HDACs), are attractive targets for cancer chemotherapy. Many drugs exert their cytotoxic effects through inhibition of these enzymes’ activity. Moreover, several reports have suggested that HDAC inhibitors (HDACi) synergize with anticancer agents directed at other targets.
Valproic acid (VPA), a short branched fatty acid used for the treatment of epilepsy, has emerged as a promising drug for cancer treatment showing antineoplastic activities against both solid and hematologic malignancies mediated by HDACs inhibition.
A phase II multicenter study reported that the combination of VPA with 5-azacytidine, a DNA-methyltransferase inhibitor, is active and safe in patients with myelodysplastic syndromes (MDS) with a poor prognosis. In addition, the combination of VPA with either fludarabine or cladribine, two purine nucleoside analogues acting as RR allosteric inhibitors, greatly increased apoptosis in chronic lymphocitic leukaemia (B-CLL) cells. Even more interestingly, VPA induced apoptosis in poor prognosis patients resistant to different type of chemotherapy.
In our previous work we found that 3’-C-methyl-adenosine (3’-Me-Ado),1 developed by us as a potent RR inhibitor with antitumor activity against both human leukaemia and carcinoma cell lines, has significant growth inhibitory and apoptotic synergistic effects in HL60 and NB4 promyelocytic leukaemia cells in combination with some hydroxamic acid–derived HDAC inhibitors2.
On the basis of this result, we pursued the development of dual-target drugs by combining the structures of 3’-Me-Ado and VPA in a single molecule. This approach has high potential to improve therapeutic efficacy of the single drug and to reduce the probability of drug induced resistance and cross resistance. The 3’-C-methyladenosine-5’-O-valproic ester and the 2’,5’-diester analog were synthesized and evaluated for their antitumor potential against a panel of human cancer cell lines. The results of this study will be presented.
References:
1-FRANCHETTI, P., et al., 2005. Antitumor activity of C-methyl-β-D-ribofuranosyladenine nucleoside ribonucleotide reductase inhibitors. Journal of Medicinal Chemistry, 48, 4983-4989.
2-GRIFANTINI, M., et al., 2009. Histone deacetylase (HDAC) inhibition modulates intracellular deoxynucleotides (DNTP) pools and potentiates the antitumor effects of the ribonucleotide reductase (RR) inhibitor 3’-methyl-adenosine (3’-Me-ADO) in promyelocitic leukaemia cell lines. 34° CONGRESSO NAZIONALE DELLA SOCIETÀ ITALIANA DI FARMACOLOGIA, P-2/4/16, Rimini, 14-17 Ottobre 2009
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
Synthesis and IMP dehydrogenase (type I and type II) inhibitory activity of isosteric NAD analogs derived from thiophenfurin and furanfurin
No full textA new tiazofurin pronucleotide: synthesis and biological evaluation of CycloSaligenyl-tiazofurin monophosphate
No full textSynthesis and biological activities of cyclosaligenyl-tiazofurin monophosphate (CycloSal-TRMP), a new tiazofurin pronucleotide, are reported. CycloSal-TRMP proved to be active in vitro against human myelogenous leukemia K562 cell line and as A1 adenosine receptor agonist
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
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