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Design, synthesis and characterization of versatile copper complexes with anticancer and catalytic activity
Full text linkAlthough copper has a long history of medical application, copper coordination compounds
have been investigated as potential anticancer agents only in the last few decades, particularly
after the discovery of cisplatin, the most widely used antitumor metallodrug. Copper, as an
essential cofactor in a number of enzymes and physiological processes, may be less toxic than
non-essential metals, such as platinum. Up to now, a great variety of copper complexes have
been tested as cytotoxic agents and found to be endowed with an antitumor activity in several
in vitro tests and few in vivo experiments. Based on these assumptions, in my PhD research
work copper was selected for the synthesis of potential metal-based anticancer drugs, that
could be suitable alternative to platinum-based drugs that are hampered by marked side
effects and chemoresistance. An important aim of this work, in the inorganic chemistry
research field, was to synthesize new species able to coordinate metals useful to obtain Cu(I)
and Cu(II) complexes with potential anticancer activity.
Copper complexes were synthesized employing bis(pyrazolyl)acetic acids (belonging to the
family of the heteroscorpionate) as ligands. This class of ligands was selected due to their
stability, flexibility and ease to be functionalized and derivatized. In fact, they were used as they
are (with the carboxylic acid group) or esterified with aliphatic alcohols (branched and not) or
bioconjugated with several biologically active compounds. For this purpose, the ligands were
conjugated with metronidazole (an antibiotic agent investigated for hypoxia-selective
cytotoxicity), NMDA-ANT (an antagonist for the N-methyl-D-aspartate receptor endowed with
micromolar cytotoxic activity on a panel of solid tumor cell lines) and lonidamine (an
antineoplastic drug) in order to obtain Cu(I) and Cu(II) complexes potentially able to exert an
anticancer activity through synergistic mechanisms of action. Additionally, to stabilize copper in
the +1 oxidation state (avoiding its oxidation) and to modulate the solubility profile of the
related copper(I) complexes, hydrophilic or lipophilic phosphanes, such as 1,3,5-triaza-7-
phosphaadamantane (PTA) and triphenylphosphine (PPh3) respectively, were used as coligands.
My main work was the design, synthesis and characterization of the ligands and related
copper complexes, both in solid state (FT-IR, elemental analysis and melting point) and in
solution (1H-,
11B-,
13C-,
31P-NMR and ESI-MS) to confirm their structure, stoichiometry and
purity. In parallel, X-ray diffraction studies were conducted on single crystals of ligands and
complexes,[b,e,g,s]
showing in some cases new and unexpected dimeric structures.[g] In addition,
the structural characterization and the study of the local coordination environment of several complexes were exploited by X-ray photoelectron spectroscopy (XPS) and X-ray absorption fine
structure (XAFS) spectroscopy (in the near edge and in the extended regions).[d,f,h,l,m,p,t]
In all the
cases, the structural investigations confirmed the hypothesized geometry of the metal center
and the coordinative fashion of the ligands.
Several new complexes and the corresponding uncoordinated ligands were evaluated for
their ability to promote cell death against a panel of human cancer cell lines, cisplatin resistant
tumor cell lines and spheroids, evaluating also cellular uptake, mechanism of action and
morphological modifications induced by the complexes once inside the tumor
cells.
[a,c,h,i,j,k,n,o,q,r,t,u]
In detail, for a series of selected precursors, ligands and Cu(I) and Cu(II)
complexes the biological activity was evaluated by means of MTT test, cellular uptake, reactive
oxygen species (ROS) production, comet assay and/or transmission electron microscope (TEM)
analyses. Summarizing, even if with slight differences, it was possible to state that the
complexes were, in general, more active that cisplatin (the drug used as reference compound),
both in 2D and 3D cell cultures, showing their effect in the low micromolar concentration, or
even lower. On the contrary, the related free ligands and precursors did not show relevant
cytotoxic activity. Interestingly, the fact that the complexes proved to be significantly more
active than cisplatin, even against three-dimensional spheroids of selected cancer cells,
increased the relevance of the in vitro results. In fact, 3D spheroids of cancer cells more closely
mimic the heterogeneity and complexity of in vivo tumors, being consequently more predictive
for in vivo results than conventional 2D cell cultures. The most frequent mechanism of action
for the tested complexes was the paraptotic one, a type of programmed cell death different
from the classical apoptosis induced by drugs such as cisplatin. This alternative programmed
cell death leads to the overcoming of the inherited or acquired cisplatin or multi-drug
resistance. Regarding the ligands esterified with aliphatic alcohols and the related copper
complexes the biological studies are still in progress but, according to the preliminary data,
these complexes seem to be very promising.
Another field of interest of my research work was the investigation of the catalytic activity of
new copper(II) compounds in the Kharasch-Sosnovsky reaction,[d,g,n]
that is a useful reaction for
the synthesis of protected allylic alcohols, via radical oxidation of olefins leaving the double
bond in its original position. In particular, the catalytic activity of the copper(II) complexes,
containing the isopropyl or hexyl ester chain, was evaluated in the Kharasch-Sosnovsky
reaction. The original reaction conditions were optimized changing several parameters and very
high yields were obtained employing the compounds containing bromide as counterion. The major limitations of this reaction, such as long reaction times, employ of benzene as solvent
and high waste of olefins, were overcome replacing the original cheap but no-so-effective CuBr
with the new synthesized Cu(II) complexes. In order to validate the generality of the method,
different olefin substrates were tested (obtaining excellent yields) and other promising Cu(II)
complexes are under evaluation as catalysts
Syntheses and biological studies of nitroimidazole conjugated heteroscorpionate ligands and related Cu(I) and Cu(II) complexes
No full textCopper(I) and copper(II) complexes of 5-nitroimidazole conjugated heteroscorpionate ligands have been synthesized. In particular, the new 2,2-bis(pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (LHMN) was synthesized by direct coupling of preformed side chain acid with 5-nitroimidazole and its coordination chemistry was investigated towards Cu(I) and Cu(II) acceptors and compared with that of the related 2,2-bis(3,5-dimethyl-1-H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (LMeMN). The copper(II) complexes [(LMeMN)2Cu]Cl2 and [(LHMN)2Cu]Cl2 were prepared by the reaction of CuCl2·2H2O with LHMN or LMeMN ligands in methanol solution. The water soluble copper(I) complexes [(LMeMN)Cu(PTA)2](PF6) and [(LHMN)Cu(PTA)2](PF6) were prepared by the reaction of Cu(CH3CN)4PF6 and 1,3,5-triaza-7-phosphaadamantane (PTA) with LHMN or LMeMN ligands in acetonitrile solution. The new Cu(I) and Cu(II) complexes as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity against 2D monolayer cultures of multiple human cancer cell lines and 3D-cultured HCT-15 colon cancer spheroids. Morphological analysis by Transmission Electron Microscopy (TEM) revealed the induction of a massive cytoplasmic vacuolization consistent with a paraptotic-like cancer cell death
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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