Author
Claudia Schmidt
Other affiliations: Technische Universität München
Bio: Claudia Schmidt is an academic researcher from Braunschweig University of Technology. The author has contributed to research in topics: Chemistry & Medicine. The author has an hindex of 12, co-authored 22 publications receiving 455 citations. Previous affiliations of Claudia Schmidt include Technische Universität München.
Topics: Chemistry, Medicine, In vivo, Combinatorial chemistry, Auranofin
Papers
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TL;DR: Gold complexes with N-heterocyclic carbene (NHC) ligands represent a promising class of metallodrugs for the treatment of cancer or infectious diseases, and antibacterial screening of the gold complexes showed a particularly high activity against Gram-positive strains, reflecting their high dependence on an intact Trx/TrxR system.
Abstract: Gold complexes with N-heterocyclic carbene (NHC) ligands represent a promising class of metallodrugs for the treatment of cancer or infectious diseases. In this report, the synthesis and the biological evaluation of halogen-containing (NHC)Au(I)Cl complexes are described. The complexes 1 and 5a-5f displayed good cytotoxic activity against tumor cells, and cellular uptake studies suggested that an intact Au-NHC fragment is essential for the accumulation of high amounts of both the metal and the NHC ligand. However, the bioavailability was negatively affected by serum components of the cell culture media and was influenced by likely transformations of the complex. One example (5d) efficiently induced apoptosis in vincristine- and daunorubicin-resistant P-glycoprotein overexpressing Nalm-6 leukemia cells. Cellular uptake studies with this compound showed that both the wildtype and resistant Nalm-6 cells accumulated comparable amounts of gold, indicating that the gold drug was not excreted by P-glycoprotein or other efflux transporters. The effective inhibition of mammalian and bacterial thioredoxin reductases (TrxR) was confirmed for all gold complexes. Antibacterial screening of the gold complexes afforded a particular high activity against Gram-positive strains, reflecting their high dependence on an intact Trx/TrxR system. This result is of particular interest as the inhibition of bacterial TrxR represents a comparably little explored mechanism of new anti-infectives.
124 citations
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TL;DR: A series of gold(i) complexes with two N-heterocyclic carbene ligands (biscarbene gold complexes) were prepared and evaluated for their effects against cancer cells and pathogenic bacteria and indicated a strong correlation between cellular bioavailability and antiproliferative effects.
Abstract: A series of gold(I) complexes with two N-heterocyclic carbene ligands (biscarbene gold complexes) were prepared and evaluated for their effects against cancer cells and pathogenic bacteria. Proliferation inhibition was observed in cancer cells and in Gram-positive bacteria, whereas Gram-negative bacteria were less sensitive towards the compounds. The protein binding and cellular uptake were quantified and the combined results indicated a strong correlation between cellular bioavailability and antiproliferative effects. The biscarbene gold complexes inhibited bacterial and mammalian TrxRs with low to moderate potency. However, based on the obtained structure–activity-relationships and the high cellular accumulation levels, TrxR inhibition can be considered as a relevant contributor to the cellular pharmacology of biscarbene gold(I) complexes.
60 citations
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TL;DR: Overall, these studies indicated that Rh(I)-NHC fragments could be used as partial structures of new antitumor agents, in particular in those drugs designed to address resistant malignant tissues.
Abstract: Rhodium(I) complexes bearing N-heterocyclic carbene (NHC) ligands have been widely used in catalytic chemistry, but there are very few reports of biological properties of these organometallics. A series of Rh(I)-NHC derivatives with 1,5-cyclooctadiene and CO as secondary ligands were synthesized, characterized, and biologically investigated as prospective antitumor drug candidates. Pronounced antiproliferative effects were noted for all complexes, along with moderate inhibitory activity of thioredoxin reductase (TrxR) and efficient binding to biomolecules (DNA, albumin). Biodistribution studies showed that the presence of albumin lowered the cellular uptake and confirmed the transport of rhodium into the nuclei. Changes in the mitochondrial membrane potential (MMP) were observed as well as DNA fragmentation in wild-type and daunorubicin- or vincristine-resistant Nalm-6 leukemia cells. Overall, these studies indicated that Rh(I)-NHC fragments could be used as partial structures of new antitumor agents, in particular in those drugs designed to address resistant malignant tissues.
60 citations
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TL;DR: Four new N-heterocyclic carbene rhodium and iridium complexes decorated with anionic or cationic pendant groups to increase their water solubility and biological activity have been synthesised and characterised and cellular uptake studies clearly confirmed that the cationIC phosphonium groups facilitated uptake, which was linked with higher biological activity.
Abstract: Four new N-heterocyclic carbene (NHC) rhodium and iridium complexes decorated with anionic or cationic pendant groups to increase their water solubility and biological activity have been synthesised and characterised. The lipophilicity of the complexes was determined and the complexes that contained cationic phosphonium groups can be considered delocalised lipophilic cations (DLCs). All complexes were tested for their antibacterial, antiparasitic and anticancer activity, with only the phosphonium-functionalised complexes showing moderate to high activity, whereas the exchange of metal from rhodium to iridium had a negligible effect. Most promising was the activity on Trypanosoma brucei, with IC50 values in the range of 150–400 nM and a selectivity index (SI) of up to 50. General toxicity on mammalian cell lines was a general problem, though, and needs to be mitigated in future work. Cellular uptake studies clearly confirmed that the cationic phosphonium groups facilitated uptake, which was linked with higher biological activity.
59 citations
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TL;DR: The novel (NHC)2Au+ complex exhibits substantially lower protein binding in combination with a strongly enhanced cytotoxic activity and represents a substantially improved and selective TrxR inhibitor compared to close structural analogues.
Abstract: Gold complexes with N-heterocyclic carbene (NHC) ligands have been attracting major attention in medicinal inorganic chemistry based on their favorable antiproliferative effects and the structural versatility of the coordinated NHC ligands. Here we present a novel complex of the type (NHC)2Au+, which represents a substantially improved and selective TrxR inhibitor compared to close structural analogues. The complex is highly stable in various solutions over 96 hours, however, comparative cellular uptake studies indicate metabolic transformations inside cells over time. A portfolio of other gold complexes (e.g. Auranofin) has been used as references in key biological assays, showing that the novel (NHC)2Au+ complex exhibits substantially lower protein binding in combination with a strongly enhanced cytotoxic activity.
53 citations
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01 Feb 1995
TL;DR: In this paper, the unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio using DFT, MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set.
Abstract: : The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg
1,652 citations
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TL;DR: A detailed account of the latest results of metal-based drugs and their potential uses in the cure of severe diseases is provided and the number of published studies in this field is huge.
560 citations
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TL;DR: This review discusses the structural details of TrxR, the functions of the Trx system, and the rational of targetingtrxR/Trx for cancer treatment, and highlights small-molecule TrXR/trx inhibitors that have potential anticancer activity and review their mechanisms of action.
276 citations
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TL;DR: In this article, the authors provide an update on the recent advances in this direction, which reflects new discoveries since the publication of their previous review, and discuss the anti-tumor properties along with the mechanisms of action for these complexes as well as possible structure-activity relationships.
267 citations