1,720,962 research outputs found
Tuning the hydrophobicity of ruthenium(ii)-arene (RAPTA) drugs to modify uptake, biomolecular interactions and efficacy
No full textAnticancer agents based on N-heterocyclic carbene (NHC) ligands: Towards compounds with multiple functionalities
No full textFull Text is available to authenticated members of The University of Auckland only.Traditional anticancer drugs have severe side effects such as those based on platinum. Therefore, other metal centres such as gold, palladium, ruthenium, rhodium and iridium are considered as potential anticancer alternatives with less side effects. Often research is framed based on targeted drug delivery to lead to more effective results and less side effects. This project focuses on the synthesis and characterisation of new organometallic complexes by using NHCs and pyridine ligands as well as the introduction of bioactive ancillary ligands. These were chosen due to their versatility and stability of their coordination compounds. Moreover, literature indicates that they are active against tumours. In total, four different series of complexes were synthesised and characterised by various methods. First, a carbene ligand series was based on a pyridinyl imidazolium scaffold to form bidentate compounds. New ruthenium and rhodium complexes were successfully synthesised and characterised by 1D/2D NMR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). Some of the structures were verified by single crystal X-ray diffraction analysis. Another series of the pro-carbene ligands were functionalised with a triphenyl phosphonium group to form monodentate ruthenium and rhodium complexes. Two structures were verified by single crystal X-ray diffraction analysis. Moreover, the N-coordinating ligand based on triphenyl(pyridine-4-ylmethyl)phosphonium hexafluorophosphate was chosen. The ruthenium and rhodium complexes were synthesised and characterised by 1D/2D NMR and electrospray ionization mass spectrometry (ESI-MS). The last one of the ligand series was N,O-chelating ligands based on the 8-oxyquinolinato platform. The ruthenium complex was synthesised and characterised by 1D/2D NMR and electrospray ionization mass spectrometry (ESI-MS)
Nitrile-functionalized pyrrolidinium ionic liquids as solvents for cross-coupling reactions involving in situ generated nanoparticle catalyst reservoirs
No full textA series of nitrile-functionalized pyrrolidinium-based ionic liquids have been prepared and characterized by spectroscopic methods and X-ray crystallography. The application of these new ionic liquids as reaction media for Suzuki and Stille C-C cross-coupling reactions has been investigated and compared with related imidazolium and pyridinium systems (including those with and without nitrile functionalities). The nature of the ionic liquid strongly influences the catalyzed reaction and it would appear that, in addition to the nitrile group, the strength of anion-cation pairing in the ionic liquid and the viscosity of the ionic liquid play critical roles. Nanoparticles are also detected following catalysis and their role, and the influence of the ionic liquid on them, is assessed. The ability to use the nitrile-functionalized pyrrolidinium-based ionic liquids diluted in other (non-functionalized) ionic liquids is also described
Maleimide-functionalized RuII(η6-arene) complexes as tumour-targeting agents
No full textFull text is available to authenticated members of The University of Auckland only.Since the first platinum-based anticancer agent cisplatin was introduced into clinics, inorganic compounds have become popular in the research field of chemotherapeutics. Different metals such as ruthenium, osmium and rhodium were studied and some complexes have already entered clinical studies. As the existing platinum-based anticancer agents show side effects, resistance and lack of selectivity, this research project aimed to develop novel ruthenium-based anticancer agents with improved selectivity for tumour sites. In this work, a series of ruthenium(II) η6-arene complexes containing maleimide functional groups and bidentate bioactive ligand systems were synthesised (Figure 1). A maleimide functional group is capable to couple with thiol groups such as cysteine residues of biomolecules for transport and exploiting selective delivery to the tumour sites due to the permeability and retention (EPR) effect. One of the promising carrier systems is human serum albumin (HSA) which is a protein target for maleimide as it has a free cysteine residue. Moreover, N-substituted 2-pyridinecarbothioamides (PCAs) act as S,N-bidentate ligands and have been reported to be bioactive as gastric mucosal protectants and show low acute toxicity in vivo. These characteristics of PCAs make them ideal candidates as ligands in metallodrug development that can be administered orally. 8-Hydroxylquinoline (8-HQ) derivatives act as N,O-bidentate ligands and have properties, such as a diverse set of bioactivities and therapeutic potential. 8-HQ complexes have properties that make them ideal candidates to overcome current limitations of chemotherapeutics. The synthesised Ru(II) complexes were characterised by melting/decomposition point analysis, NMR spectroscopy and electrospray ionisation (ESI) mass spectrometry. Furthermore, the thiol binding ability of selected complexes was studied by using L-cysteine as a model. The reaction was monitored by 1H NMR and the results showed the complexes are highly selective for thiol groups. Protein (HSA, transferrin and human serum) binding studies with a selected complex were also conducted. The reactions were monitored by size exclusion chromatography hyphenated to inductively coupled plasma mass spectrometry (SEC-UV/vis-ICP-MS) and the results showed the complex is capable of binding to both HSA and transferrin
Metallodrugs and Proteins: Expanding the Bioanalytical Toolkit to Investigate the Metallation of Biomolecules
No full textMetal-based anticancer agents are a widely used class of chemotherapeutics. Ru complexes show increasing promise over traditional Pt-based drugs as selective treatment options. Organometallic compounds with π-bound ligands are highly versatile in terms of structure and biomolecule binding profiles. To investigate reactions with biomolecules, a bioanalytical toolkit, primarily comprised of crystallography and mass spectrometry, was employed to understand the broad range of interactions observed of metal-based anticancer agents. To characterise interactions between cisplatin and human serum albumin, matrix-matched standards were prepared for use in LA–ICP-MS after separation with polyacrylamide gel electrophoresis. The use of such standards made from HSA and cisplatin adducts proved to be an effective way to analyse the amount of platinum bound to albumin. Dimeric Ru/Os(arene) compounds were investigated for their interactions with the model protein hen egg white lysozyme (HEWL). Protein crystallography, ion mobility mass spectrometry, differential scanning calorimetry, and dynamic light scattering revealed that the metal centre and the labile ligands determines the amount of adducts formed. To extend the study of the interactions between HEWL and metal complexes, Me- and Bn-substituted N-heterocyclic carbene (NHC) complexes were investigated. Binding studies between [RuII(η6-p-cymene)(NHC)Cl2] and HEWL revealed that p-cymene was cleaved concomitant to bidentate coordination of Ru to Arg14-His15 and oxidation of RuII to RuIII, as confirmed by electron paramagnetic resonance spectroscopy. To determine the structure-(re)activity profiles of NHC complexes with alternate metal centres, Os/Rh/Ir compounds were investigated. The Rh(η5-pentamethylcyclopentadienyl) analogue also bound at His15 upon substitution of the NHC ligand. In contrast, the Os(η6-p-cymene) and Ir(η5-pentamethylcyclopentadienyl) analogues underwent chlorido/side chain ligand exchange with Asn103 and Asp101, respectively. The complexes were investigated for their inhibition of thioredoxin reductase as a potential target and only the Rh analogues were effective. Furthermore, the lipophilicity influenced the cytotoxicity of all studied NHC complexes. These results suggest that small changes to organometallic complexes affect the biological activity and interactions with proteins. [RuII(η6-p-cymene)(N-fluorophenyl-2-pyridinecarbothioamide)Cl]Cl is highly cytotoxic and was shown to be selective towards the large scaffold protein plectin. Molecular mass spectrometry was used to determine which part of plectin forms adducts with the Ru complex. The most prominent binding partner was identified as the construct containing the first two spectrin repeats. The bioanalytical studies used here to explore the interactions between metal-based anticancer agents and proteins demonstrates that small changes to the metal centre or the attached ligands affect the amounts and type of adducts formed. The investigations lay the foundation for the development of more specific metallodrugs
Interactions of the carrier ligands of antidiabetic metal complexes with human serum albumin: a combined spectroscopic and separation approach with molecular modeling studies
No full textThe specific binding of carrier ligands of antidiabetic vanadium(IV) and zinc(II) complexes into drug binding pockets of human serum albumin (HSA) has been investigated via displacement reactions of site markers such as warfarin and dansylglycine by different spectroscopic (fluorescence, circular dichroism, NMR) and separation methods (capillary zone electrophoresis, ultrafiltration-UV). Conditional stability constants of the ligands were calculated for the binding at sites I and II of HSA. Binding site I was found to be the primary binding site for 2,6-pyridine dicarboxylic acid (dipic) and picolinic acid (pic), and site II for 6-methylpicolinic acid (6-Mepic) and maltol, although dipic, 6-Mepic and pic displace both site markers at differing extents. The experimental data is complemented by protein-ligand docking calculations for dipic and 6-Mepic which support the observations
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
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