1,720,960 research outputs found
Development of multifunctional anticancer agents: design, synthesis and evaluation of hybrid compounds containing kinase inhibitor moieties
Full text linkCancer is a complex and a multiple-genes involved disease; for this reason it can not be treated or cured with a single drug modulating the biological function of a single target. The innovation related to multi-targeted drugs, combining the activity of different cancer progression relevant targets, became a burgeoning research topic. Drugs that act on multiple targets can enhance efficacy and reduce chemo-resistance that causes disease relapse and metastasis and remains the main obstacle to cancer therapy. One of the main target nowadays are tyrosine kinases (TKs); since most protein kinases stimulate cell growth and proliferation, cell survival and migration, they can, if overexpressed, amplified or constitutively active, assume oncogenic properties. Other ideal biological targets are enzymes as histone deacetylases (HDAC) and mitochondrial functions. Herein we present the development and the preliminary evaluation of new Abl/HDAC inhibitors bearing the pyrido-pyrimidine main scaffold; the functionalization of the most active compounds with metal ions (i.e. Zn2+, Cu2+ and Fe3+); the development of novel multi-kinase inhibitors bearing the 4-anilinopyrimidine scaffold; the development of novel cKIT/wtRET/V804MRET inhibitors bearing the 4-anilinopyridine scaffold. Besides, the development of multi-kinase inhibitors endowed with antifibrotic properties as well as novel topoisomerase inhibitors are reported
Targeting kinases with anilinopyrimidines: discovery of N-phenyl-N’-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of Type III receptor tyrosine kinase subfamily
No full textKinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi-target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multi tyrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis the kinase profiling and the biological evaluation of a set of novel 4-anilinopyrimidines as promising anticancer compounds. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds.
Among synthesized compounds, N-phenyl-N’-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives targeted some members of type III receptor tyrosine kinase family. In particular, compound 24 was identified as a selective dual KIT/PDGFRbeta inhibitor. The compound was more cytotoxic than sunitinib against A549 and PxPC3 human cancer cell lines, and showed a preferential antiproliferative activity toward neoplastic rather than HEK293 non-tumor cells.
Overall, our data suggested that the 4-anilino-6-phenylpyrimidines constitute a promising class of subfamily selective inhibitors of Type III RTKs subfamily. These results are of remarkably importance since, despite the huge interest in identifying subfamily selective kinase inhibitors, poorly toxic and highly active as antitumor agents, nowadays there is still a paucity of reports investigating their antitumor activity
Biphenylaminoquinazolines as novel dual inhibitors of tyrosine kinases and tubulin polymerization: synthesis, SARs and anticancer properties
No full textThe discovery of the anticancer drugs erlotinib and gefitinib in the early 2000’s prompted intensive research on 4-anilinoquinazoline compounds. The main biomolecular target for this class of compounds remains the Epidermal Growth Factor Receptor (EGFR), although some compounds do not show high selectivity for it. Cell cycle experiments with our previously reported 4-biphenylaminoquinazolines multi-tyrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors.
Novel 4-biarylaminoquinazoline analogues were synthesized and evaluated as inhibitors of several tyrosine kinases and of tubulin. While previous compounds acted as dual inhibitors, the new heterobiaryl analogues possessed only anti-tubulin properties and targeted the colchicine site. On the contrary, the absence of a dioxygenated fused ring led to compounds inactive against tubulin polymerization.
The most interesting compounds were cytotoxic in both OVCAR-8 (human ovarian carcinoma) and NCI/ADR-RES (human ovarian carcinoma P-glycoprotein overexpressing) cell lines at nanomolar concentration
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
Targeting kinases with anilinopyrimidines: Discovery of N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of class III receptor tyrosine kinase subfamily
Full text linkKinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent
literature has highlighted the importance of multi target kinase inhibitors, although a correct
balance between specificity and non-specificity is required. In this view, the discovery of multityrosine
kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the
synthesis and the preliminary kinase profiling of a set of novel 4-anilinopyrimidines. Among the
synthesized compounds, the N-phenyl-N’-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively
targeted some members of class III receptor tyrosine kinase family. Starting from the structure of
hit compound 19 we synthesized a further compound with an improved affinity toward the class III
receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro
and in vivo in a murine solid tumor model. Molecular modeling simulations were used in order to
rationalize the behavior of the title compounds
Novel benzoquinoline derivatives via unpredicted condensation of ethyl propiolate and naphthylamines: Synthesis and topoisomerase inhibition activity
No full textAn unpredicted condensation of naphthylamine with two molecules of ethyl propiolate yields directly carbethoxy benzoquinoline in high yield. Some benzoquinoline carboxamide derivatives with protonatable side chains were then synthesized and evaluated for antiproliferative activity on human tumor cell lines. The most active compound (7a) demonstrated to intercalate into DNA and to inhibit the relaxation activity mediated by topoisomerase II
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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