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EFFECTS OF METAL(III) COORDINATION ON BIOLOGICAL ACTIVITY OF 2,2'-BIPYRIDYL-6-CARBOTHIOAMIDE (BPYTA), A POTENT R2 RIBONUCLEOTIDE REDUCTASE INHIBITOR
No full textInvestigations from our laboratory have led to the development of 2,2'-bipyridyl-6-carbothioamide (BPYTA), that demonstrated a powerful cytotoxicity for rodent and human tumoral cell lines and for peripheral blasts from patients suffering from acute leukemia.1 The BPYTA cytotoxic effect is mainly due to the inhibition of ribonucleotide reductase (RR), the enzyme responsible for reductive conversion of ribo- to deoxyribonucleotides that has long been regarded as an important target for therapies aiming to control pathologies that depend strongly on DNA replication. BPYTA is characterized by chelating properties because of the N*-N*-S* tridentate coordination system similar to that of α-(N)-heterocyclic carboxaldehyde thiosemicarbazones, whose metal complexes have been extensively investigated. However, the properties of BPYTA-complexes and thiosemicarbazone-complexes are not identical. Among the transition-metal(II) complexes with BPYTA, the iron chelate [BPYTA-Fe(II), molar ratio 2:1], is the active form of the ligand which destroys the tyrosyl radical of RR small subunit R2, while other transition-metal complexes resulted in significant differences in biochemical effects of the ligand and, perhaps, also for its mechanism of action.2
In the present study we report on the effects of metal(III) coordination on the pharmacological properties of BPYTA. In particular, new complexes with gallium(III) and iron(III) with the general formula [M(L)2]+ have been prepared and investigated for their biological activity. Moreover, a novel improved and inexpensive synthesis of BPYTA has been developed.
References
1-NOCENTINI, G., et al., 1993. 2,2'-Bipyridyl-6-carbothioamide and its ferrous complex: their in vitro antitumoral activity related to the inhibition of ribonucleotide reductase R2 subunit. Cancer Research, 53, 19-26.
2-FRANCHETTI, P., et al., 1988. Metal(II) complexes of 2,2'-bipyridyl-6-carbothioamide as antitumor and antifungal agents. European Journal of Medicinal Chemistry, 23, 301-305
Metal drugs and the anticancer immune response
Full text linkThe immune system deploys a multitude of innate and adaptive mechanisms not only to ward off pathogens but also to prevent malignant transformation ("immune surveillance"). Hence, a clinically apparent tumor already reflects selection for those malignant cell clones capable of evading immune recognition ("immune evasion"). Metal drugs, besides their well-investigated cytotoxic anticancer effects, massively interact with the cancer-immune interface and can reverse important aspects of immune evasion. This topic has recently gained intense attention based on combination approaches with anticancer immunotherapy (e.g., immune checkpoint inhibitors), a strategy recently delivering first exciting results in clinical settings. This review summarizes the promising but still extremely fragmentary knowledge on the interplay of metal drugs with the fidelity of anticancer immune responses but also their role in adverse effects. It highlights that, at least in some cases, metal drugs can induce long-lasting anticancer immune responses. Important steps in this process comprise altered visibility and susceptibility of cancer cells toward innate and adaptive immunity, as well as direct impacts on immune cell populations and the tumor microenvironment. On the basis of the gathered information, we suggest initiating joint multidisciplinary programs to implement comprehensive immune analyses into strategies to develop novel and smart anticancer metal compounds
Mechanisms underlying reductant-induced reactive oxygen species formation by anticancer copper(II) compounds
No full textIntracellular generation of reactive oxygen
species (ROS) via thiol-mediated reduction of copper(II) to
copper(I) has been assumed as the major mechanism
underlying the anticancer activity of copper(II) complexes.
The aim of this study was to compare the anticancer
potential of copper(II) complexes of Triapine (3-amino-
pyridine-2-carboxaldehyde thiosemicarbazone; currently in
phase II clinical trials) and its terminally dimethylated
derivative with that of 2-formylpyridine thiosemicarbazone
and that of 2,2' -bipyridyl-6-carbothioamide. Experiments
on generation of oxidative stress and the influence of biologically relevant reductants (glutathione, ascorbic acid) on
the anticancer activity of the copper complexes revealed
that reductant-dependent redox cycling occurred mainly
outside the cells, leading to generation and dismutation of
superoxide radicals resulting in cytotoxic amounts of H2O2.
However, without extracellular reductants only weak
intracellular ROS generation was observed at IC50 levels,
suggesting that cellular thiols are not involved in copper-
complex-induced oxidative stress. Taken together, thiol-
induced intracellular ROS generation might contribute to
the anticancer activity of copper thiosemicarbazone complexes but is not the determining factor
Development and biological investigations of hypoxia-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib
No full textDespite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dramatically reduced ALK and c-MET kinase-inhibitory potential. Furthermore, the prodrugs showed high stability in serum and release of crizotinib in an enzymatic nitroreductase-based cleavage assay was observed for prodrug A. The in vitro activity of both prodrugs was investigated against ALK- and c-MET-dependent or –overexpressing cells, revealing a distinct hypoxia-dependent activation for prodrug A. Finally, inhibition of c-MET phosphorylation and cell proliferation could also be proven in vivo. In summary of the theoretical, chemical and biological studies, prodrug derivatization of the 2-aminopyridine position can be considered as a promising strategy to reduce the side effects and improve the anticancer activity of crizotinib
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
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