341 results on '"Angela Casini"'
Search Results
2. Aquaglyceroporin Modulators as Emergent Pharmacological Molecules for Human Diseases
- Author
-
Catarina Pimpão, Darren Wragg, Inês V. da Silva, Angela Casini, and Graça Soveral
- Subjects
aquaporin ,glycerol permeability ,functional assays ,computational methods ,regulation ,expression modulators ,Biology (General) ,QH301-705.5 - Abstract
Aquaglyceroporins, a sub-class of aquaporins that facilitate the diffusion of water, glycerol and other small uncharged solutes across cell membranes, have been recognized for their important role in human physiology and their involvement in multiple disorders, mostly related to disturbed energy homeostasis. Aquaglyceroporins dysfunction in a variety of pathological conditions highlighted their targeting as novel therapeutic strategies, boosting the search for potent and selective modulators with pharmacological properties. The identification of selective inhibitors with potential clinical applications has been challenging, relying on accurate assays to measure membrane glycerol permeability and validate effective functional blockers. Additionally, biologicals such as hormones and natural compounds have been revealed as alternative strategies to modulate aquaglyceroporins via their gene and protein expression. This review summarizes the current knowledge of aquaglyceroporins’ involvement in several pathologies and the experimental approaches used to evaluate glycerol permeability and aquaglyceroporin modulation. In addition, we provide an update on aquaglyceroporins modulators reported to impact disease, unveiling aquaglyceroporin pharmacological targeting as a promising approach for innovative therapeutics.
- Published
- 2022
- Full Text
- View/download PDF
3. Bio-based and bio-inspired adhesives from animals and plants for biomedical applications
- Author
-
Theresa M. Lutz, Ceren Kimna, Angela Casini, and Oliver Lieleg
- Subjects
Bioglue ,Slime ,Adhesive ,Carbohydrate ,Protein ,Glycoprotein ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
With the “many-headed” slime mold Physarum polycelphalum having been voted the unicellular organism of the year 2021 by the German Society of Protozoology, we are reminded that a large part of nature's huge variety of life forms is easily overlooked – both by the general public and researchers alike. Indeed, whereas several animals such as mussels or spiders have already inspired many scientists to create novel materials with glue-like properties, there is much more to discover in the flora and fauna. Here, we provide an overview of naturally occurring slimy substances with adhesive properties and categorize them in terms of the main chemical motifs that convey their stickiness, i.e., carbohydrate-, protein-, and glycoprotein-based biological glues. Furthermore, we highlight selected recent developments in the area of material design and functionalization that aim at making use of such biological compounds for novel applications in medicine – either by conjugating adhesive motifs found in nature to biological or synthetic macromolecules or by synthetically creating (multi-)functional materials, which combine adhesive properties with additional, problem-specific (and sometimes tunable) features.
- Published
- 2022
- Full Text
- View/download PDF
4. Optimization of the Pharmacokinetic Profile of [99mTc]Tc-N4-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp Sequence
- Author
-
Thomas Günther, Matthias Konrad, León Stopper, Jan-Philip Kunert, Sebastian Fischer, Roswitha Beck, Angela Casini, and Hans-Jürgen Wester
- Subjects
GRPR ,technetium-99m ,pharmacophore-modified compounds ,prostate cancer ,breast cancer ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Current radiolabeled gastrin-releasing peptide receptor (GRPR) ligands usually suffer from high accumulation in GRPR-positive organs (pancreas, stomach), limiting tumor-to-background contrast in the abdomen. In novel N4-bombesin derivatives this was addressed by substitutions at the Gln7-Trp8 site within the MJ9 peptide (H-Pip5-phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) either by homoserine (Hse7), β-(3-benzothienyl) alanine (Bta8) or α-methyl tryptophan (α-Me-Trp8), with the aim of optimizing pharmacokinetics. We prepared and characterized the peptide conjugates 6-carboxy-1,4,8,11-tetraazaundecane (N4)-asp-MJ9, N4-asp-[Bta8]MJ9, N4-[Hse7]MJ9 and N4-[α-Me-Trp8]MJ9, and evaluated these compounds in vitro (GRPR affinity via IC50,inverse; internalization; lipophilicity via logD7.4) and in vivo (biodistribution and μSPECT/CT studies at 1 h post injection (p.i.) in PC-3 tumor-bearing CB17-SCID mice). 99mTc-labeling resulted in radiochemical yields (RCYs) > 95%. All 99mTc-labeled MJ9 analogues showed comparable or higher GRPR affinity than the external reference [99mTc]Tc-Demobesin 4. Receptor-bound fractions were noticeably higher than that of the reference. Despite a slightly enhanced lipophilicity, all novel MJ9 derivatives revealed improved in vivo pharmacokinetics compared to the reference. The Bta8-modified ligand revealed the most favorable tumor-to-abdomen contrast at 1 h p.i. Substitutions at the Gln7-Trp8 site within GRPR ligands hold great potential to modify pharmacokinetics for improved imaging.
- Published
- 2022
- Full Text
- View/download PDF
5. Identifying and validating the presence of Guanine-Quadruplexes (G4) within the blood fluke parasite Schistosoma mansoni.
- Author
-
Holly M Craven, Riccardo Bonsignore, Vasilis Lenis, Nicolo Santi, Daniel Berrar, Martin Swain, Helen Whiteland, Angela Casini, and Karl F Hoffmann
- Subjects
Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
Schistosomiasis is a neglected tropical disease that currently affects over 250 million individuals worldwide. In the absence of an immunoprophylactic vaccine and the recognition that mono-chemotherapeutic control of schistosomiasis by praziquantel has limitations, new strategies for managing disease burden are urgently needed. A better understanding of schistosome biology could identify previously undocumented areas suitable for the development of novel interventions. Here, for the first time, we detail the presence of G-quadruplexes (G4) and putative quadruplex forming sequences (PQS) within the Schistosoma mansoni genome. We find that G4 are present in both intragenic and intergenic regions of the seven autosomes as well as the sex-defining allosome pair. Amongst intragenic regions, G4 are particularly enriched in 3´ UTR regions. Gene Ontology (GO) term analysis evidenced significant G4 enrichment in the wnt signalling pathway (p
- Published
- 2021
- Full Text
- View/download PDF
6. Investigation of Solvatomorphism and Its Photophysical Implications for Archetypal Trinuclear Au3(1-Methylimidazolate)3
- Author
-
Shengyang Guan, David C. Mayer, Christian Jandl, Sebastian J. Weishäupl, Angela Casini, and Alexander Pöthig
- Subjects
cyclic trinuclear complex ,photoluminescence ,aurophilic interactions ,Organic chemistry ,QD241-441 - Abstract
A new solvatomorph of [Au3(1-Methylimidazolate)3] (Au3(MeIm)3)—the simplest congener of imidazolate-based Au(I) cyclic trinuclear complexes (CTCs)—has been identified and structurally characterized. Single-crystal X-ray diffraction revealed a dichloromethane solvate exhibiting remarkably short intermolecular Au⋯Au distances (3.2190(7) Å). This goes along with a dimer formation in the solid state, which is not observed in a previously reported solvent-free crystal structure. Hirshfeld analysis, in combination with density functional theory (DFT) calculations, indicates that the dimerization is generally driven by attractive aurophilic interactions, which are commonly associated with the luminescence properties of CTCs. Since Au3(MeIm)3 has previously been reported to be emissive in the solid-state, we conducted a thorough photophysical study combined with phase analysis by means of powder X-ray diffraction (PXRD), to correctly attribute the photophysically active phase of the bulk material. Interestingly, all investigated powder samples accessed via different preparation methods can be assigned to the pristine solvent-free crystal structure, showing no aurophilic interactions. Finally, the observed strong thermochromism of the solid-state material was investigated by means of variable-temperature PXRD, ruling out a significant phase transition being responsible for the drastic change of the emission properties (hypsochromic shift from 710 nm to 510 nm) when lowering the temperature down to 77 K.
- Published
- 2021
- Full Text
- View/download PDF
7. Editorial: Supramolecular Metal-Based Entities for Biomedical and Biological Applications
- Author
-
Angela Casini and James D. Crowley
- Subjects
supramolecular complex ,MOF (Metal-Organic-Framework) ,metallacages ,metallacycle complexes ,therapy ,drug delivery systems ,Chemistry ,QD1-999 - Published
- 2019
- Full Text
- View/download PDF
8. Exo-Functionalized Metallacages as Host-Guest Systems for the Anticancer Drug Cisplatin
- Author
-
Ben Woods, Margot N. Wenzel, Thomas Williams, Sophie R. Thomas, Robert L. Jenkins, and Angela Casini
- Subjects
metallacages ,supramolecular coordination complexes ,water solubility ,host-guest chemistry ,cisplatin ,Chemistry ,QD1-999 - Abstract
Within the framework of designing new self-assembled metallosupramolecular architectures for drug delivery, seven [Pd2L4]4+ metallacages (L = 2,6-bis(pyridine-3-ylethynyl)pyridine) featuring different groups in exo-position, selected to enhance the cage solubility in aqueous environment, were synthesized. Thus, carboxylic acids, sugars, and PEG groups were tethered to the bispyridyl ligands directly or via disulfide bond formation, as well as via click chemistry. The ligands and respective cages were characterized by different methods, including NMR spectroscopy and high-resolution electrospray mass spectrometry (HR-ESI-MS). While the two ligands featuring carboxylic acid-functionalized groups showed improved solubility in water, the other ligands were soluble only in organic solvents. Unfortunately, all the respective self-assembled cages were also insoluble in water. Afterwards, the encapsulation properties of the anticancer drug cisplatin in selected [Pd2L4]X4 cages (X = NO3-, BF4-) were studied by 1H, 1H DOSY, and 195Pt NMR spectroscopy. The effect of the counter ions as well as of the polarity of the solvent in the drug encapsulation process were also investigated, and provided useful information on the host-guest properties of these experimental drug delivery systems. Our results provide further experimental support for previous studies that suggest the desolvation of guests from surrounding solvent molecules and the resulting solvent rearrangement may actually be the primary driving force for determining guest binding affinities in metallacages, in the absence of specific functional group interactions.
- Published
- 2019
- Full Text
- View/download PDF
9. Insights into the Selectivity Mechanisms of Grapevine NIP Aquaporins
- Author
-
Farzana Sabir, Antonella Di Pizio, Maria C. Loureiro-Dias, Angela Casini, Graça Soveral, and Catarina Prista
- Subjects
nodulin 26-like intrinsic proteins ,grapevine ,ar/R selectivity filter ,site-directed mutagenesis ,substrate selectivity ,homology modeling ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Nodulin 26-like intrinsic proteins (NIPs) of the plant aquaporin family majorly facilitate the transport of physiologically relevant solutes. The present study intended to investigate how substrate selectivity in grapevine NIPs is influenced by the aromatic/arginine (ar/R) selectivity filter within the pore and the possible underlying mechanisms. A mutational approach was used to interchange the ar/R residues between grapevine NIPs (VvTnNIP1;1 with VvTnNIP6;1, and VvTnNIP2;1 with VvTnNIP5;1). Their functional characterization by stopped-flow spectroscopy in Saccharomyces cerevisiae revealed that mutations in residues of H2/H5 helices in VvTnNIP1;1 and VvTnNIP6;1 caused a general decline in membrane glycerol permeability but did not impart the expected substrate conductivity in the mutants. This result suggests that ar/R filter substitution could alter the NIP channel activity, but it was not sufficient to interchange their substrate preferences. Further, homology modeling analyses evidenced that variations in the pore radius combined with the differences in the channel’s physicochemical properties (hydrophilicity/hydrophobicity) may drive substrate selectivity. Furthermore, yeast growth assays showed that H5 residue substitution alleviated the sensitivity of VvTnNIP2;1 and VvTnNIP5;1 to As, B, and Se, implying importance of H5 sequence for substrate selection. These results contribute to the knowledge of the overall determinants of substrate selectivity in NIPs.
- Published
- 2020
- Full Text
- View/download PDF
10. Relevance of Copper and Organic Cation Transporters in the Activity and Transport Mechanisms of an Anticancer Cyclometallated Gold(III) Compound in Comparison to Cisplatin
- Author
-
Sarah Spreckelmeyer, Margot van der Zee, Benoît Bertrand, Ewen Bodio, Stefan Stürup, and Angela Casini
- Subjects
organometallic gold compounds ,cisplatin ,cancer ,drug transporters ,organic cation transporters ,copper transporters ,Chemistry ,QD1-999 - Abstract
The molecular mechanisms of toxicity and cellular transport of anticancer metallodrugs, including platinum-based agents, have not yet been fully elucidated. The aim of our study was to investigate the relevance of copper transporters (CTR1 and ATP7A/B), organic cation transporters (OCT2) and the multidrug and toxin extrusion proteins (MATE) in the intracellular accumulation of a novel organometallic cytotoxic Au(III) compound in cancer cells in comparison to cisplatin. Specifically, the synthesis and characterization of the gold complex [Au(pyb-H)(PPh2Ar)Cl]PF6 (PPh2Ar = 3-[4-(diphenylphosphino)phenyl]-7-methoxy-2H-chromen-2-one] (1), featuring a coumarin ligand endowed with “smart” fluorescence properties, have been achieved. Initially, the cytotoxic effects of both cisplatin and 1 were studied in a small panel of human cancer cells, and against a non-tumorigenic cell line in vitro. Thus, the human ovarian cancer cell line A2780 and its cisplatin resistant variant A2780cisR, were selected, being most sensitive to the treatment of the gold complex. Co-incubation of the metallodrugs with CuCl2 (a CTR1 substrate) increased the cytotoxic effects of both the Au(III) complex and cisplatin; while co-incubation with cimetidine (inhibitor of OCT2 and MATE) showed some effect only after 72 h incubation. ICP-MS (Inductively Coupled Plasma Mass Spectrometry) analysis of the cell extracts showed that co-incubation with CuCl2 increases Au and Cu accumulation in both cancer cell lines, in accordance with the enhanced antiproliferative effects. Conversely, for cisplatin, no increase in Pt content could be observed in both cell lines after co-incubation with either CuCl2 or cimetidine, excluding the involvement of CTR1, OCT2, and MATE in drug accumulation and overall anticancer effects. This result, together with the evidence for increased Cu content in A2780 cells after cisplatin co-treatment with CuCl2, suggests that copper accumulation is the reason for the observed enhanced anticancer effects in this cell line. Moreover, metal uptake studies in the same cell lines indicate that both 1 and cisplatin are not transported intracellularly by CTR1 and OCT2. Finally, preliminary fluorescence microscopy studies enabled the visualization of the sub-cellular distribution of the gold compound in A2780 cells, suggesting accumulation in specific cytosolic components/organelles.
- Published
- 2018
- Full Text
- View/download PDF
11. Mechanistic Insights into Gold Organometallic Compounds and their Biomedical Applications
- Author
-
Sophie Jürgens and Angela Casini
- Subjects
Chemistry ,QD1-999 - Published
- 2017
- Full Text
- View/download PDF
12. Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview beyond Cisplatin
- Author
-
Sarah Spreckelmeyer, Chris Orvig, and Angela Casini
- Subjects
metal complexes ,Pt drugs ,membrane transporters ,uptake ,efflux ,accumulation ,mechanism of action ,cancer ,copper ,Organic chemistry ,QD241-441 - Abstract
The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes (e.g., Ru Au and Ir). Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.
- Published
- 2014
- Full Text
- View/download PDF
13. Gold(III) Pyridine-Benzimidazole Complexes as Aquaglyceroporin Inhibitors and Antiproliferative Agents
- Author
-
Brech Aikman, Margot N. Wenzel, Andreia F. Mósca, Andreia de Almeida, Wim T. Klooster, Simon J. Coles, Graça Soveral, and Angela Casini
- Subjects
Gold(III) complexes ,pyridine benzimidazole ,aquaporins ,cancer ,stopped-flow spectroscopy ,antiproliferative activity ,Inorganic chemistry ,QD146-197 - Abstract
Gold compounds have been proven to be novel and versatile tools for biological applications, including as anticancer agents. Recently, we explored the potential of Au(III) complexes with bi-dentate N-donor ligands as inhibitors of the membrane water and glycerol channels aquaporins (AQPs), involved in different physiological and pathophysiological pathways. Here, eight new Au(III) complexes featuring a pyridine-benzimidazole scaffold have been synthesized and characterized via different methods. The stability of all the compounds in aqueous solution and their reactivity with glutathione have been investigated by UV⁻visible spectroscopy. The Au(III) compounds, tested for their AQPs inhibition properties in human Red Blood Cells (hRBC), are potent and selective inhibitors of AQP3. Furthermore, the compounds’ antiproliferative effects have been studied in a small panel of human cancer cells expressing AQP3. The complexes show only very moderate anticancer effects in vitro and are mostly active against the melanoma A375 cells, with marked expression of AQP3 at the level of the nuclear membrane. In general, the AQP3 inhibition properties of these complexes hold promises to develop them as chemical probes to study the function of this protein isoform in biological systems.
- Published
- 2018
- Full Text
- View/download PDF
14. Molecular Basis of Aquaporin-7 Permeability Regulation by pH
- Author
-
Andreia F. Mósca, Andreia de Almeida, Darren Wragg, Ana P. Martins, Farzana Sabir, Stefano Leoni, Teresa F. Moura, Catarina Prista, Angela Casini, and Graça Soveral
- Subjects
aquaporin ,aquaglyceroporin ,AQP7 ,pH ,yeast ,regulation ,water and glycerol permeability ,Cytology ,QH573-671 - Abstract
The aquaglyceroporin AQP7, a family member of aquaporin membrane channels, facilitates the permeation of water and glycerol through cell membranes and is crucial for body lipid and energy homeostasis. Regulation of glycerol permeability via AQP7 is considered a promising therapeutic strategy towards fat-related metabolic complications. Here, we used a yeast aqy-null strain for heterologous expression and functional analysis of human AQP7 and investigated its regulation by pH. Using a combination of in vitro and in silico approaches, we found that AQP7 changes from fully permeable to virtually closed at acidic pH, and that Tyr135 and His165 facing the extracellular environment are crucial residues for channel permeability. Moreover, instead of reducing the pore size, the protonation of key residues changes AQP7’s protein surface electrostatic charges, which, in turn, may decrease glycerol’s binding affinity to the pore, resulting in decreased permeability. In addition, since some pH-sensitive residues are located at the monomer-monomer interface, decreased permeability may result from cooperativity between AQP7’s monomers. Considering the importance of glycerol permeation via AQP7 in multiple pathophysiological conditions, this mechanism of hAQP7 pH-regulation may help the design of selective modulators targeting aquaglyceroporin-related disorders.
- Published
- 2018
- Full Text
- View/download PDF
15. Targeting aquaporin function: potent inhibition of aquaglyceroporin-3 by a gold-based compound.
- Author
-
Ana Paula Martins, Alessandro Marrone, Antonella Ciancetta, Ana Galán Cobo, Miriam Echevarría, Teresa F Moura, Nazzareno Re, Angela Casini, and Graça Soveral
- Subjects
Medicine ,Science - Abstract
Aquaporins (AQPs) are membrane channels that conduct water and small solutes such as glycerol and are involved in many physiological functions. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of several diseases. Until today few AQP inhibitors have been described as suitable candidates for clinical development. Here we report on the potent inhibition of AQP3 channels by gold(III) complexes screened on human red blood cells (hRBC) and AQP3-transfected PC12 cells by a stopped-flow method. Among the various metal compounds tested, Auphen is the most active on AQP3 (IC(50) = 0.8±0.08 µM in hRBC). Interestingly, the compound poorly affects the water permeability of AQP1. The mechanism of gold inhibition is related to the ability of Au(III) to interact with sulphydryls groups of proteins such as the thiolates of cysteine residues. Additional DFT and modeling studies on possible gold compound/AQP adducts provide a tentative description of the system at a molecular level. The mapping of the periplasmic surface of an homology model of human AQP3 evidenced the thiol group of Cys40 as a likely candidate for binding to gold(III) complexes. Moreover, the investigation of non-covalent binding of Au complexes by docking approaches revealed their preferential binding to AQP3 with respect to AQP1. The high selectivity and low concentration dependent inhibitory effect of Auphen (in the nanomolar range) together with its high water solubility makes the compound a suitable drug lead for future in vivo studies. These results may present novel metal-based scaffolds for AQP drug development.
- Published
- 2012
- Full Text
- View/download PDF
16. Metal-based Anticancer Agents
- Author
-
Angela Casini, Anne Vessières, Samuel M Meier-Menches, Angela Casini, Anne Vessières, Samuel M Meier-Menches and Angela Casini, Anne Vessières, Samuel M Meier-Menches, Angela Casini, Anne Vessières, Samuel M Meier-Menches
- Published
- 2019
17. Elucidating the Multimodal Anticancer Mechanism of an Organometallic Terpyridine Platinum(II) N-Heterocyclic Carbene Complex against Triple-Negative Breast Cancer In Vitro and In Vivo
- Author
-
Jing-Jing Zhang, Qi-Jie Xu, Claudia Schmidt, Mohamed A. Abu el Maaty, Jinglin Song, Chunqiu Yu, Jun Zhou, Kang Han, Hao Sun, Angela Casini, Ingo Ott, and Stefan Wölfl
- Subjects
Drug Discovery ,Molecular Medicine - Published
- 2023
18. Beyond Metal-Arenes: Monocarbonyl Ruthenium(II) Catalysts for Transfer Hydrogenation Reactions in Cancer Cells
- Author
-
Denise Lovison, Tobias Berghausen, Sophie Thomas, Jonathan Robson, Markus Drees, Christian Jandl, Patrick Mollik, Dominik Halter, Walter Baratta, and Angela Casini
- Abstract
With the aim to design new water-soluble organometallic Ru(II) complexes acting as anticancer agents catalysing transfer hydrogenation (TH) reactions with biomolecules, we have synthesized four Ru(II) monocarbonyl complexes (1-4) featuring the 1,4-bis(diphenylphosphino)butane (dppb) ligand and different bidentate nitrogen (N^N) ligands, of general formula [Ru(OAc)CO(dppb)(N^N)]n (n = +1, 0; OAc = acetate). The compounds have been characterised by different methods, including 1H and 31P NMR spectroscopy, electrochemistry as well as single crystals X-ray diffraction in the case of 1 and 4. The compounds have also been studied for their hydrolysis in aqueous environment, and for the catalytic regioselective reduction of NAD+ to 1,4-NADH in aqueous solution with sodium formate as hydride source. Moreover, the stoichiometric and catalytic oxidation of 1,4-NADH have also been investigated by UV-Visible spectrophotometry and NMR spectroscopy. Overall, initial structure-activity relationships could be inferred which point towards the influence of the extension of the aromatic N^N ligand in the cationic complexes 1-3 on the TH in both reduction/oxidation processes. The neutral complex 4, featuring a picolinamidate N^N ligand, stands out as the most active catalyst for the reduction of NAD+, while being completely inactive towards NADH oxidation. The compound can also convert pyruvate into lactate in the presence of formate, albeit with scarce efficiency. In any case, for all compounds, Ru(II) hydride intermediates could be observed and even isolated in the case of complexes 1-3. Together, insight from the kinetic and electrochemical characterization suggests that, in the case of Ru(II) complexes 1-3, catalytic NADH oxidation sees the H-transfer from 1,4-NADH as the rate limiting step, whereas for NAD+ hydrogenation with formate as the H-donor, the rate limiting step is the transfer of the ruthenium hydride to the NAD+ substrate. The latter is further modulated by the presence of di-cationic aquo- or mono-cationic hydroxo-species of complexes 1-3. Instead, compound 4, stable with respect to hydrolysis in aqueous solution, appears to operate via a different mechanism. Finally, the anticancer activity and ability to form reactive oxygen species (ROS) of complexes 1-3 have been studied in cancerous and non-tumorigenic cells in vitro. Noteworthy, the conversion of aldehydes to alcohols could be achieved by the three Ru(II) catalysts in living cells, as assessed by fluorescence microscopy. Furthermore, the formation of Ru(II) hydride intermediate upon treatment of cancer cell extracts with complex 3 has been detected by 1H NMR spectroscopy. Overall, this study paves the way to the application of non-arene based organometallic complexes as TH catalysts in biological environment.
- Published
- 2023
19. Mitochondria-targeted metal–organic frameworks for cancer treatment
- Author
-
Tanveer A. Tabish, Mian Zahid Hussain, Roland A. Fischer, and Angela Casini
- Subjects
Mechanics of Materials ,Mechanical Engineering ,General Materials Science ,Condensed Matter Physics - Published
- 2023
20. Organometallic Pillarplexes that bind DNA 4-way Holliday Junctions and Forks
- Author
-
James S. Craig, Larry Melidis, Hugo D. Williams, Samuel J. Dettmer, Alexandra A. Heidecker, Philipp J. Altmann, Shengyang Guan, Callum Campbell, Douglas F. Browning, Roland K.O. Sigel, Silke Johannsen, Ross T. Egan, Brech Aikman, Angela Casini, Alexander Pöthig, and Michael J. Hannon
- Abstract
Holliday 4-way junctions are key to important biological DNA processes (insertion, recombination and repair) and are dynamic structures which adopt either open or closed conformations, with the open conformation being the biologically active form. Tetracationic metallo-supramolecular pillarplexes display aryl faces about a cylindrical core giving them an ideal structure to interact with the central cavities of open DNA junctions. Combining experimental studies and MD simulations we show that an Au pillarplex can bind DNA 4-way junctions (Holliday junctions) in their open form, a binding mode not accessed by synthetic agents before. The Au pillarplexes can bind designed 3-way junctions too but their large size leads them to open up and expand that junction, disrupting the base pairing which manifests in an increase in hydrodynamic size and a lower junction thermal stability. At high loading they re-arrange both 4-way and 3-way junctions into Y-shaped DNA forks to increase the available junction-like binding sites. The structurally related Ag pillarplexes show similar DNA junction binding behaviour, but a lower solution stability. This pillarplex binding contrasts with (but complements) that of the metallo-supramolecular cylinders, which prefer 3-way junctions and we show can rearrange 4-way junctions into 3-way junction structures. The pillarplexes’ ability to bind open 4-way junctions creates exciting possibilities to modulate and switch such structures in biology, as well as in synthetic nucleic acid nanostructures where they are key interconnecting components. Studies in human cells, confirm that the pillarplexes do reach the nucleus, with antiproliferative activity at levels similar to those of cisplatin. The findings provide a new roadmap for targeting higher order junction structures using a metallo-supramolecular approach, as well as expanding the toolbox available to design bioactive junction-binders into organometallic chemistry.Abstract Figure
- Published
- 2023
21. Supramolecular metal-based molecules and materials for biomedical applications
- Author
-
Angela Casini, Roland A. Fischer, and Guillermo Moreno-Alcántar
- Subjects
Metal ,Materials science ,visual_art ,Supramolecular chemistry ,visual_art.visual_art_medium ,Molecule ,Nanotechnology - Published
- 2023
22. 'Dynamical Docking' of Cyclic Dinuclear Au(I) Bis-N-heterocyclic Complexes Facilitates Their Binding to G-Quadruplexes
- Author
-
Clemens Kaußler, Darren Wragg, Claudia Schmidt, Guillermo Moreno-Alcántar, Christian Jandl, Johannes Stephan, Roland A. Fischer, Stefano Leoni, Angela Casini, Riccardo Bonsignore, Kaußler, Clemen, Wragg, Darren, Schmidt, Claudia, Moreno-Alcántar, Guillermo, Jandl, Christian, Stephan, Johanne, Fischer, Roland A., Leoni, Stefano, Casini, Angela, and Bonsignore, Riccardo
- Subjects
Inorganic Chemistry ,G-quadruplex ,Physical and Theoretical Chemistry - Abstract
With the aim to improve the design of metal complexes as stabilizers of noncanonical DNA secondary structures, namely, G-quadruplexes (G4s), a series of cyclic dinuclear Au(I) N-heterocyclic carbene complexes based on xanthine and benzimidazole ligands has been synthesized and characterized by various methods, including X-ray diffraction. Fluorescence resonance energy transfer (FRET) and CD DNA melting assays unraveled the compounds’ stabilization properties toward G4s of different topologies of physiological relevance. Initial structure–activity relationships have been identified and recognize the family of xanthine derivatives as those more selective toward G4s versus duplex DNA. The binding modes and free-energy landscape of the most active xanthine derivative (featuring a propyl linker) with the promoter sequence cKIT1 have been studied by metadynamics. The atomistic simulations evidenced that the Au(I) compound interacts noncovalently with the top G4 tetrad. The theoretical results on the Au(I) complex/DNA Gibbs free energy of binding were experimentally validated by FRET DNA melting assays. The compounds have also been tested for their antiproliferative properties in human cancer cells in vitro, showing generally moderate activity. This study provides further insights into the biological activity of Au(I) organometallics acting via noncovalent interactions and underlines their promise for tunable targeted applications by appropriate chemical modifications.
- Published
- 2022
23. Competitive Profiling of Ligandable Cysteines in Staphylococcus aureus with an Organogold Compound
- Author
-
Claudia Schmidt, Angela Casini, Michael Zollo, Riccardo Bonsignore, Stephan Hacker, and Claudia Schmidt, Michael Zollo, Riccardo Bonsignore, Angela Casini, Stephan M. Hacker
- Subjects
Staphylococcus aureus ,Materials Chemistry ,Metals and Alloys ,Ceramics and Composites ,Cysteine ,General Chemistry ,Organogold Compounds ,Catalysis ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials - Abstract
With the idea of exploiting metal-templated reactions to achieve selective modification of cysteines in proteins for antibacterial applications, an organometallic cyclometalated Au(III) compound was explored in a competitive chemoproteomic approach based on the isoDTB-ABPP (isotopically labelled desthiobiotin azide-activity-based protein profiling) technology in S. aureus cell extracts. In this way, more than 100 ligandable cysteines where identified, of which 10 were close to functional sites of proteins encoded by essential genes indicating potential for antibiotic development. Interestingly, more than 50% of the identified ligandable sites were not engaged by organic α-chloroacetamides in a previous study, indicating that organometallic compounds expand the ligandable space in bacteria. A selected interaction identified by isoDTB-ABPP was validated using an enzyme activity assay, and intact protein mass spectrometry showed that cysteine arylation of an unprecedented target occurs with the studied compound. The obtained results constitute the proof-of-concept that this family of organogold compounds has potential for therapeutic protein targeting via selective, covalent modification of cysteine residues in bacteria. Looking more broadly, our study demonstrates that the targets of cyclometalated gold compounds can be studied proteome-wide with competitive residue-specific chemoproteomics enabling the expansion of the known ligandable proteome to sites that can be addressed with this compound class.
- Published
- 2022
24. Bioinorganic supramolecular coordination complexes and their biomedical applications
- Author
-
Luis Guillermo Moreno Alcántar and Angela Casini
- Subjects
Structural Biology ,Genetics ,Biophysics ,In a Nutshell ,drug delivery ,imaging ,metallacages ,self-assembly ,supramolecular coordination complexes ,therapy ,Cell Biology ,Molecular Biology ,Biochemistry ,ddc - Abstract
The field of Bioinorganic Supramolecular Chemistry is an emerging research area including metal-based supramolecules resulting from coordination-driven self-assembly (CDSA), whereby metal ions and organic ligands can be easily linked by metal-ligand bonds via Lewis' acid/base interactions. The focus of this 'In a Nutshell' review will be on the family of supramolecular coordination complexes, discrete entities formed by CDSA, which have recently captured widespread attention as a new class of versatile multifunctional materials with broad biological applications including molecular recognition, biosensing, therapy, imaging and drug delivery. Herein, we provide a summary of the state-of-the-art use of these systems in biomedicine, with some selected representative examples, as well as our visions of the challenges and possible directions in the field.
- Published
- 2022
25. PET Imaging of Self-Assembled
- Author
-
Raúl, Cosialls, Cristina, Simó, Salvador, Borrós, Vanessa, Gómez-Vallejo, Claudia, Schmidt, Jordi, Llop, Ana B, Cuenca, and Angela, Casini
- Abstract
To advance the design of self-assembled metallosupramolecular architectures as new generation theranostic agents, the synthesis of
- Published
- 2022
26. Mitochondrial targeting properties of new gold and copper complexes in breast cancer
- Author
-
Valeria Scalcon, Alessandra Folda, Riccardo Bonsignore, Jana Aupic, Alessandra Magistrato, Angela Casini, and Maria Pia Rigobello
- Subjects
Physiology (medical) ,Biochemistry - Published
- 2023
27. Wirt‐Gast‐Wechselwirkungen in einer Serie isoretikulärer Metall‐organischer Gerüststrukturen für molekulare photokatalytische CO 2 ‐Reduktion
- Author
-
Roland A. Fischer, Angela Casini, Julien Warnan, Natalia B. Shustova, Johanna Haimerl, Bernhard Rieger, Philip M. Stanley, Christopher Thomas, Alexander Urstoeger, and Michael Schuster
- Subjects
Materials science ,General Medicine - Published
- 2021
28. Host–Guest Interactions in a Metal–Organic Framework Isoreticular Series for Molecular Photocatalytic CO 2 Reduction
- Author
-
Christopher Thomas, Roland A. Fischer, Bernhard Rieger, Julien Warnan, Natalia B. Shustova, Michael Schuster, Alexander Urstoeger, Johanna Haimerl, Philip M. Stanley, and Angela Casini
- Subjects
010405 organic chemistry ,Chemistry ,Supramolecular chemistry ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Catalysis ,ddc ,0104 chemical sciences ,Chemical engineering ,Photocatalysis ,Particle ,Photosensitizer ,Metal-organic framework ,Selectivity ,Hybrid material - Abstract
A strategy to improve homogeneous molecular catalyst stability, efficiency, and selectivity is the immobilization on supporting surfaces or within host matrices. Herein, we examine the co-immobilization of a CO2 reduction catalyst [ReBr(CO)3 (4,4'-dcbpy)] and a photosensitizer [Ru(bpy)2 (5,5'-dcbpy)]Cl2 using the isoreticular series of metal-organic frameworks (MOFs) UiO-66, -67, and -68. Specific host pore size choice enables distinct catalyst and photosensitizer spatial location-either at the outer MOF particle surface or inside the MOF cavities-affecting catalyst stability, electronic communication between reaction center and photosensitizer, and consequently the apparent catalytic rates. These results allow for a rational understanding of an optimized supramolecular layout of catalyst, photosensitizer, and host matrix.
- Published
- 2021
29. Interfering with Metabolic Profile of Triple‐Negative Breast Cancers Using Rationally Designed Metformin Prodrugs
- Author
-
Meng Rui Chang, Angela Casini, Zhi Chiaw Lim, Markella Zannikou, Kai Ren Chong, Vladimir Kushnarev, Irina V. Balyasnikova, Maria V. Babak, Hui Min Tang, Jian Yu Yap, Peter Rapta, Lisa Reichert, Wee Han Ang, Samuel M. Meier-Menches, and Petra Heffeter
- Subjects
Transplantation, Heterologous ,Drug Evaluation, Preclinical ,Molecular Conformation ,Antineoplastic Agents ,Triple Negative Breast Neoplasms ,Phenformin ,010402 general chemistry ,01 natural sciences ,Catalysis ,chemistry.chemical_compound ,Mice ,Breast cancer ,Coordination Complexes ,Cell Line, Tumor ,medicine ,Autophagy ,Cytotoxic T cell ,Animals ,Humans ,Prodrugs ,010405 organic chemistry ,Drug discovery ,business.industry ,General Chemistry ,General Medicine ,Prodrug ,medicine.disease ,Ligand (biochemistry) ,Metformin ,0104 chemical sciences ,chemistry ,Cancer research ,Gold ,business ,Energy Metabolism ,Metabolic profile ,medicine.drug - Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel AuIII cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated AuIII fragment. The lead complex 3met was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro-survival responses to induce deadly metabolic catastrophe.
- Published
- 2021
30. Radiolabeled supramolecular coordination complexes targeted to somatostatin receptors
- Author
-
Sandra Deiser, Thomas Günther, and Angela Casini
- Subjects
Cancer Research ,Molecular Medicine ,Radiology, Nuclear Medicine and imaging - Published
- 2022
31. Blood–brain barrier penetrating peptide-based radioligands targeting the EGFR:EGFRvIII receptors
- Author
-
Franziska Schuderer, Angela Casini, and João Domingos Correia
- Subjects
Cancer Research ,Molecular Medicine ,Radiology, Nuclear Medicine and imaging - Published
- 2022
32. Bottom-up synthesis of water-soluble gold nanoparticles stabilized by N-Heterocyclic carbenes: From structural characterization to applications
- Author
-
Sophie R. Thomas, Wenjie Yang, David J. Morgan, Thomas E. Davies, Jiao Jiao Li, Roland A. Fischer, Jun Huang, Nikolaos Dimitratos, Angela Casini, Thomas, Sophie R, Yang, Wenjie, Morgan, David J, Davies, Thomas E, Li, Jiao Jiao, Fischer, Roland A, Huang, Jun, Dimitratos, Nikolao, and Casini, Angela
- Subjects
spectroscopy ,photothermal therapy ,Au nanoparticle ,Organic Chemistry ,Metal Nanoparticles ,Water ,General Chemistry ,catalysi ,Wastewater ,Ligands ,Catalysis ,ddc ,Nitrophenols ,Humans ,Colloids ,Gold ,Research Article ,Research Articles ,Au nanoparticles ,catalysis ,N-heterocyclic carbenes ,03 Chemical Sciences ,N-heterocyclic carbene ,Methane - Abstract
N-heterocyclic carbenes (NHCs) have become attractive ligands for functionalizing gold nanoparticle surfaces with applications ranging from catalysis to biomedicine. Despite their great potential, NHC stabilized gold colloids (NHC@AuNPs) are still scarcely explored and further efforts should be conducted to improve their design and functionalization. Here, the 'bottom-up' synthesis of two water-soluble gold nanoparticles (AuNP-1 and AuNP-2) stabilized by hydrophilic mono- and bidentate NHC ligands is reported together with their characterization by various spectroscopic and analytical methods. The NPs showed key differences likely to be due to the selected NHC ligand systems. Transmission electron microscopy (TEM) images showed small quasi-spherical and faceted NHC@AuNPs of similar particle size (ca. 2.3-2.6 nm) and narrow particle size distribution, but the colloids featured different ratios of Au(I)/Au(0) by X-ray photoelectron spectroscopy (XPS). Furthermore, the NHC@AuNPs were supported on titania and fully characterized. The new NPs were studied for their catalytic activity towards the reduction of nitrophenol substrates, the reduction of resazurin and for their photothermal efficiency. Initial results on their application in photothermal therapy (PTT) were obtained in human cancer cells in vitro. The aforementioned reactions represent important model reactions towards wastewater remediation, bioorthogonal transformations and cancer treatment.
- Published
- 2022
33. Cyclodextrin metal-organic frameworks and derivatives: recent developments and applications
- Author
-
Sarah V. Dummert, Haneesh Saini, Mian Zahid Hussain, Khushboo Yadava, Kolleboyina Jayaramulu, Angela Casini, and Roland A. Fischer
- Subjects
Cyclodextrins ,Drug Delivery Systems ,General Chemistry ,Porosity ,Catalysis ,Metal-Organic Frameworks - Abstract
While there is a tremendous amount of scientific research on metal organic frameworks (MOFs) for gas storage/separation, catalysis and energy storage, the development and application of biocompatible MOFs still poses major challenges. In general, they can be synthesised from various biocompatible linkers and metal ions but particularly cyclodextrins (CDs) as cyclic oligosaccharides are an astute choice for the former. Although the field of CD-MOF materials is still in the early stages and their design and fabrication comes with many hurdles, the benefits coming from CDs built in a porous framework are exciting. Versatile host-guest complexation abilities, high encapsulation capacity and hydrophilicity are among the valuable properties inherent to CDs and offer extended and novel applications to MOFs. In this review, we provide an overview of the state-of-the-art synthesis, design, properties and applications of these materials. Initially, a rationale for the preparation of CD-based MOFs is provided, based on the chemical and structural properties of CDs and including their advantages and disadvantages. Further on, the review exhaustively surveys CD-MOF based materials by categorising them into three sub-classes, namely (i) CD-MOFs, (ii) CD-MOF hybrids, obtained
- Published
- 2022
34. Front Cover: Indenyl and Allyl Palladate Complexes Bearing N ‐Heterocyclic Carbene Ligands: an Easily Accessible Class of New Anticancer Drug Candidates (Eur. J. Inorg. Chem. 16/2022)
- Author
-
Thomas Scattolin, Ilenia Pessotto, Enrico Cavarzerani, Vincenzo Canzonieri, Laura Orian, Nicola Demitri, Claudia Schmidt, Angela Casini, Enrica Bortolamiol, Fabiano Visentin, Flavio Rizzolio, and Steven P. Nolan
- Subjects
Inorganic Chemistry - Published
- 2022
35. Bioconjugate Supramolecular Pd2+ Metallacages Penetrate the Blood Brain Barrier In Vitro and In Vivo
- Author
-
Lurdes Gano, Marco Cavaco, João D. G. Correia, Darren Wragg, Vera Neves, Vera F. C. Ferreira, Tânia S. Morais, Claudia Schmidt, Rúben D M Silva, Filipa Mendes, Angela Casini, and Ben Woods
- Subjects
Pharmacology ,chemistry.chemical_classification ,Biodistribution ,Bioconjugation ,010405 organic chemistry ,Ligand ,Organic Chemistry ,Biomedical Engineering ,Supramolecular chemistry ,Pharmaceutical Science ,Bioengineering ,Peptide ,02 engineering and technology ,021001 nanoscience & nanotechnology ,01 natural sciences ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug delivery ,Peptide synthesis ,Biophysics ,0210 nano-technology ,Biotechnology - Abstract
The biomedical application of discrete supramolecular metal-based structures, specifically self-assembled metallacages, is still an emergent field of study. Capitalizing on the knowledge gained in recent years on the development of 3-dimensional (3D) metallacages as novel drug delivery systems and theranostic agents, we explore here the possibility to target [Pd2L4]4+ cages (L = 3,5-bis(3-ethynylpyridine)phenyl ligand) to the brain. In detail, a new water-soluble homoleptic cage (CPepH3) tethered to a blood brain barrier (BBB)-translocating peptide was synthesized by a combination of solid-phase peptide synthesis (SPPS) and self-assembly procedures. The cage translocation efficacy was assessed by inductively coupled mass spectrometry (ICP-MS) in a BBB cellular model in vitro. Biodistribution studies of the radiolabeled cage [[99mTcO4]- ⊂ CPepH3] in the CD1 mice model demonstrate its brain penetration properties in vivo. Further DFT studies were conducted to model the structure of the [[99mTcO4]- ⊂ cage] complex. Moreover, the encapsulation capabilities and stability of the cage were investigated using the [ReO4]- anion, the "cold" analogue of [99mTcO4]-, by 1H NMR spectroscopy. Overall, our study constitutes another proof-of-concept of the unique potential of supramolecular coordination complexes for modifying the physiochemical and biodistribution properties of diagnostic species.
- Published
- 2021
36. Highly-fluorescent BODIPY-functionalised metallacages as drug delivery systems
- Author
-
Brech Aikman, Riccardo Bonsignore, Ben Woods, Daniel Doellerer, Riccardo Scotti, Claudia Schmidt, Alexandra A. Heidecker, Alexander Pöthig, Edward J. Sayers, Arwyn T. Jones, Angela Casini, Synthetic Organic Chemistry, Nanomedicine & Drug Targeting, Aikman B., Bonsignore R., Woods B., Doellerer D., Scotti R., Schmidt C., Heidecker A.A., Pothig A., Sayers E.J., Jones A.T., and Casini A.
- Subjects
Boron Compounds ,Inorganic Chemistry ,Drug Delivery Systems ,Cell Line, Tumor ,Humans ,Cisplatin ,Palladium - Abstract
With the aim of designing new metallosupramolecular architectures for drug delivery, research has focused on porous 3-dimensional (3D)-metallacages able to encapsulate cytotoxic agents protecting them from metabolism while targeting them to cancer sites. Here, two self-assembled [Pd2L4]4+ cages (CG1 and CG2) featuring 3,5-bis(3-ethynylpyridine)phenyl ligands (L) exo-functionalised with dipyrromethene (BODIPY) groups have been synthesised and characterised by different methods, including NMR spectroscopy and mass spectrometry. 1H NMR spectroscopy studies shows that the cages are able to encapsulate the anticancer drug cisplatin in their hydrophobic cavity, as evidenced by electrostatic potential (ESP) analysis based on XRD studies. The stability of the cages in an aqueous environment, and in the presence of the intracellular reducing agent glutathione, has been confirmed by UV-visible absorption spectroscopy. The luminescence properties of the cages enabled the investigation of their cellular uptake and intracellular localisation in human cancer cells by confocal laser scanning microscopy. In melanoma A375 cells, cage CG1 is taken up via active transport and endocytic trafficking studies show little evidence of transport through the early endosome while the cages accumulated in melanosomes rather than lysosomes. The antiproliferative activity of the lead cage was investigated in A375 together with two breast cancer cell lines, SK-BR-3 and MCF7. While the cage per se is non-cytotoxic, very different antiproliferative effects with respect to free cisplatin were evidenced for the [(cisplatin)2⊂CG1·BF4] complex in the various cell lines, which correlate with its different intracellular localisation profiles. The obtained preliminary results provide a new hypothesis on how the subcellular localisation of the cage affects the cisplatin intracellular release.
- Published
- 2022
37. Competitive profiling of ligandable cysteines in
- Author
-
Claudia, Schmidt, Michael, Zollo, Riccardo, Bonsignore, Angela, Casini, and Stephan M, Hacker
- Subjects
Staphylococcus aureus ,Cysteine ,Organogold Compounds - Abstract
With the idea of exploiting metal templated C-S bond forming reactions to achieve modification of cysteines in bacterial proteins, a cyclometalated Au(III) compound was explored in a competitive chemoproteomic approach in
- Published
- 2022
38. Metals in Medicine
- Author
-
Edith C. Glazer and Angela Casini
- Subjects
Inorganic Chemistry - Published
- 2022
39. Comparing the Antileishmanial Activity of Gold(I) and Gold(III) Compounds in L. amazonensis and L. braziliensis in Vitro
- Author
-
Riccardo Bonsignore, Danilo C. Miguel, Angela Casini, Leticia B. Rosa, Karen Minori, Minori K., Rosa L.B., Bonsignore Riccardo., Casini A., and Miguel D.C.
- Subjects
Stereochemistry ,Antiprotozoal Agents ,amastigotes ,01 natural sciences ,Biochemistry ,Mice ,Gold iii ,Parasitic Sensitivity Tests ,Gold Compounds ,Drug Discovery ,gold compounds ,medicine ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,Amastigote ,leishmaniasis ,Cells, Cultured ,EC50 ,Leishmania ,Pharmacology ,Mice, Inbred BALB C ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Communication ,Organic Chemistry ,Leishmaniasis ,medicine.disease ,biology.organism_classification ,Leishmania braziliensis ,Communications ,In vitro ,ddc ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Molecular Medicine ,promastigotes ,Organogold Compounds ,Intracellular - Abstract
Abstract: A series of mononuclear coordination or organometallic AuI/AuIII complexes (1–9) have been comparatively studied in vitro for their antileishmanial activity against promastigotes and amastigotes, the clinically relevant parasite form, of Leishmania amazonensis and Leishmania braziliensis. One of the cationic AuI bis‐N‐heterocyclic carbenes (3) has low EC50 values (ca. 4 μM) in promastigotes cells and no toxicity in host macrophages. Together with two other AuIII complexes (6 and 7), the compound is also extremely effective in intracellular amastigotes from L. amazonensis. Initial mechanistic studies include an evaluation of the gold complexes′ effect on L. amazonensis’ plasma membrane integrity., Gold bullets against leishmaniasis: A small library of AuI/AuIII complexes has been investigated for their antileishmanial activity in the promastigote and amastigote forms of the parasite. The most active and selective compounds could effectively disrupt parasite membrane permeability in vitro. Initial structure‐activity relationships were established that might lead to the design of novel drug scaffolds for leishmaniasis treatment.
- Published
- 2020
40. Targeted imaging of integrins in cancer tissues using photocleavable Ru(ii) polypyridine complexes as mass-tags
- Author
-
Erika R Amstalden van Hove, Geny M. M. Groothuis, Jiaying Han, Peter Horvatovich, Cornelia J Verhoeven, Rainer Bischoff, Hjalmar P. Permentier, Shanshan Song, Gyorgy B. Halmos, Angela Casini, Leonie Beljaars, Jing Sun, Analytical Biochemistry, Molecular Pharmacology, Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Nanomedicine & Drug Targeting, Medicinal Chemistry and Bioanalysis (MCB), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and E&H: Environmental Bioanalytical Chemistry
- Subjects
DESORPTION ,Alpha-v beta-3 ,Pyridines ,Integrin ,010402 general chemistry ,Mass spectrometry ,Peptides, Cyclic ,01 natural sciences ,Mass Spectrometry ,Catalysis ,Epitope ,Mass spectrometry imaging ,HIGH-SPATIAL-RESOLUTION ,chemistry.chemical_compound ,SDG 3 - Good Health and Well-being ,Materials Chemistry ,medicine ,Humans ,ALPHA-V-BETA-3 ,biology ,010405 organic chemistry ,Chemistry ,TRANSMISSION GEOMETRY ,RUTHENIUM ,Metals and Alloys ,Cancer ,General Chemistry ,Integrin alphaVbeta3 ,medicine.disease ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Tissue sections ,SPECTROMETRY ,Head and Neck Neoplasms ,Ceramics and Composites ,biology.protein ,Biophysics ,Human cancer - Abstract
Targeted epitope-based mass spectrometry imaging (MSI) utilizes laser cleavable mass-tags bound to targeting moieties for detecting proteins in tissue sections. Our work constitutes the first proof-of-concept of a novel laser desorption ionization (LDI)-MSI strategy using photocleavable Ru(ii) polypyridine complexes as mass-tags for imaging of integrins avß3 in human cancer tissues.
- Published
- 2020
41. Design Strategies and Medicinal Applications of Metal-Peptidic Bioconjugates
- Author
-
Angela Casini and Samuel M. Meier-Menches
- Subjects
Pharmacology ,Drug Carriers ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,technology, industry, and agriculture ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,02 engineering and technology ,021001 nanoscience & nanotechnology ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Metal ,Metals ,visual_art ,visual_art.visual_art_medium ,Animals ,Humans ,Peptides ,0210 nano-technology ,Biotechnology - Abstract
The conjugation of metal-based scaffolds to peptides, proteins, or antibodies allows the systemic targeting of these payloads to specific locations in the body, such as target cells/tissues (e.g., cancer) and subcellular compartments, for either therapy or imaging. This Topical Review includes an overview of the available chemical strategies to achieve metal-peptidic bioconjugates for biomedical applications, focusing on the types of chemical functionalities used to tether the drug to the peptide directly or indirectly. Central to all the possible approaches is the development of highly efficient and selective bioconjugation reactions that operate under mild, peptide-compatible conditions. For each strategy, selected examples are highlighted with particular emphasis to the studies reporting the therapeutic effects of the metal-peptidic conjugates in the treatment of cancer. Overall, some of the herewith discussed cases clearly hold promise for translation into clinically meaningful applications in the field of targeted therapeutics. Nevertheless, novel chemical approaches enabling the chemoselective metalation of specific residues in peptides under biologically friendly conditions, as well as the design of stimuli-responsive bioconjugates, are still expected to emerge. Certainly, the peculiar biorthogonal reactivity of metallodrugs provides an enlarged toolbox of opportunities for bioconjugation. Therefore, we outline a number of possible future directions and applications.
- Published
- 2020
42. Organometallic Chemistry of Gold-Based Drugs
- Author
-
Angela Casini and Claudia Schmidt
- Subjects
chemistry.chemical_compound ,Chemistry ,Combinatorial chemistry ,Organometallic chemistry - Published
- 2022
43. Indenyl and Allyl Palladate Complexes Bearing N ???Heterocyclic Carbene Ligands: an Easily Accessible Class of New Anticancer Drug Candidates
- Author
-
Thomas Scattolin, Ilenia Pessotto, Enrico Cavarzerani, Vincenzo Canzonieri, Laura Orian, Nicola Demitri, Claudia Schmidt, Angela Casini, Enrica Bortolamiol, Fabiano Visentin, Flavio Rizzolio, and Steven P. Nolan
- Subjects
Settore CHIM/03 - Chimica Generale e Inorganica ,SCREENING MODEL ,Allyl and indenyl palladium complexes ,NHC ,DERIVATIVES ,INHIBITION ,OVARIAN-CANCER ,REACTIVITY ,Anticancer activity ,Mechanochemistry ,N-heterocyclic carbenes ,Thioredoxin reductase inhibition ,Inorganic Chemistry ,ENERGY ,Chemistry ,DESIGN ,AGENTS - Abstract
The mechanochemical syntheses of allyl and indenyl palladate complexes are reported. All compounds were obtained in quantitative yields and microanalytically pure without the need of any workup. These complexes are stable in chlorinated and polar (DMSO or DMSO/H2O solutions) solvents. In chlorinated solvents, they appear as ionic pairs of which crystals suitable for single X-ray diffraction studies have been obtained. Bonding and solvation properties are rationalized through scalar relativistic DFT calculations. Moreover, most complexes showed excellent cytotoxicity towards ovarian cancer cell lines, with IC50 values comparable or lower than cisplatin. The potent anticancer activity of two IPrCl and IPr*-based palladate complexes was examined in a high-grade serous ovarian cancer (HGSOC) patient-derived tumoroid. Moreover, the inhibition of the antioxidant enzyme thioredoxin reductase (TrxR) was noticed, and structure-activity relationships could be derived, suggesting the ROS detoxifying system is involved in the mode of action.
- Published
- 2022
44. PET Imaging of Self-Assembled 18F-Labelled Pd2L4 Metallacages for Anticancer Drug Delivery
- Author
-
Raúl Cosialls, Cristina Simó, Salvador Borrós, Vanessa Gómez‐Vallejo, Claudia Schmidt, Jordi Llop, Ana B. Cuenca, and Angela Casini
- Subjects
Organic Chemistry ,Research Article ,Research Articles ,ammonium trifluoroborates ,cisplatin ,drug delivery ,metallacages ,PET imaging ,self-assembly ,General Chemistry ,Catalysis ,ddc - Published
- 2021
45. Aquaglyceroporin Modulators as Emergent Pharmacological Molecules for Human Diseases
- Author
-
Catarina Pimpão, Darren Wragg, Inês V. da Silva, Angela Casini, and Graça Soveral
- Subjects
aquaporin ,computational methods ,functional assays ,QH301-705.5 ,expression modulators ,glycerol permeability ,regulation ,Biology (General) ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Molecular Biology ,Biochemistry ,ddc - Abstract
Aquaglyceroporins, a sub-class of aquaporins that facilitate the diffusion of water, glycerol and other small uncharged solutes across cell membranes, have been recognized for their important role in human physiology and their involvement in multiple disorders, mostly related to disturbed energy homeostasis. Aquaglyceroporins dysfunction in a variety of pathological conditions highlighted their targeting as novel therapeutic strategies, boosting the search for potent and selective modulators with pharmacological properties. The identification of selective inhibitors with potential clinical applications has been challenging, relying on accurate assays to measure membrane glycerol permeability and validate effective functional blockers. Additionally, biologicals such as hormones and natural compounds have been revealed as alternative strategies to modulate aquaglyceroporins via their gene and protein expression. This review summarizes the current knowledge of aquaglyceroporins’ involvement in several pathologies and the experimental approaches used to evaluate glycerol permeability and aquaglyceroporin modulation. In addition, we provide an update on aquaglyceroporins modulators reported to impact disease, unveiling aquaglyceroporin pharmacological targeting as a promising approach for innovative therapeutics.
- Published
- 2021
46. C−C Cross-Couplings from a Cyclometalated Au(III) C∧ N Complex: Mechanistic Insights and Synthetic Developments
- Author
-
Mathilde Rigoulet, Angela Casini, Giampaolo Barone, Sophie R. Thomas, Didier Bourissou, Riccardo Bonsignore, Alexander Pöthig, Christian Jandl, Bonsignore R., Thomas S.R., Rigoulet M., Jandl C., Pothig A., Bourissou D., Barone G., Casini A., Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Laboratoire Hétérochimie Fondamentale et Appliquée (LHFA), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Palermo - University of Palermo, ANR-19-CE07-0037,Gold-III,Chimie de l'or(III)(2019), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), and Technical University of Munich (TUM)
- Subjects
Coordination sphere ,Heteroatom ,010402 general chemistry ,01 natural sciences ,Catalysis ,Reductive elimination ,NMR spectroscopy ,Nucleophile ,cross-coupling ,Reactivity (chemistry) ,Full Paper ,010405 organic chemistry ,Chemistry ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,Organic Chemistry ,reductive elimination ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,[CHIM.CATA]Chemical Sciences/Catalysis ,Full Papers ,Transition state ,0104 chemical sciences ,gold cyclometalated complexes ,Crystallography ,Zinc ,Settore CHIM/03 - Chimica Generale E Inorganica ,Gold ,Two-dimensional nuclear magnetic resonance spectroscopy ,organometallics - Abstract
In recent years, the reactivity of gold complexes was shown to extend well beyond π‐activation and to hold promises to achieve selective cross‐couplings in several C−C and C−E (E=heteroatom) bond forming reactions. Here, with the aim of exploiting new organometallic species for cross‐coupling reactions, we report on the Au(III)‐mediated C(sp2)−C(sp) occurring upon reaction of the cyclometalated complex [Au(CCH2N)Cl2] (1, CCH2N=2‐benzylpyridine) with AgPhCC. The reaction progress has been monitored by NMR spectroscopy, demonstrating the involvement of a number of key intermediates, whose structures have been unambiguously ascertained through 1D and 2D NMR analyses (1H, 13C, 1H‐1H COSY, 1H‐13C HSQC and 1H‐13C HMBC) as well as by HR‐ESI‐MS and X‐ray diffraction studies. Furthermore, crystallographic studies have serendipitously resulted in the authentication of zwitterionic Au(I) complexes as side‐products arising from cyclization of the coupling product in the coordination sphere of gold. The experimental work has been paralleled and complemented by DFT calculations of the reaction profiles, providing valuable insight into the structure and energetics of the key intermediates and transition states, as well as on the coordination sphere of gold along the whole process. Of note, the broader scope of the cross‐coupling at the Au(III) CCH2N centre has also been demonstrated studying the reaction of 1 with C(sp2)‐based nucleophiles, namely vinyl and heteroaryl tin and zinc reagents. These reactions stand as rare examples of C(sp2)−C(sp2) cross‐couplings at Au(III)., The mechanism of C(sp2)−C(sp) coupling templated by the Au(III) cyclometalated complex [Au(CCH2N)Cl2] has been investigated. By tuning the reaction conditions and monitoring its progress by NMR, a number of intermediate species involved in the reductive elimination process could be isolated and characterised by different spectroscopic and analytical methods, including XRD, as well as by DFT studies.
- Published
- 2021
47. Connecting copper and cancer: from transition metal signalling to metalloplasia
- Author
-
Michael J. Petris, Michael L. Schilsky, Justin R. Cross, Q Ping Dou, Gina M. DeNicola, Ashley I. Bush, Peng Yuan, Roman S. Polishchuk, Sanjeev Gupta, Donita C. Brady, Stephen G. Kaler, Katherine J. Franz, Vishal M. Gohil, Nicholas K. Tonks, Vivek Mittal, Svetlana Lutsenko, Linda Van Aelst, Eva J Ge, Dan Xi, Martina Ralle, Angela Casini, Christopher J. Chang, Linda T. Vahdat, and Paul A. Cobine
- Subjects
Kinase ,Cell growth ,Autophagy ,Regulator ,Computational biology ,ULK2 ,ULK1 ,Biology ,Article ,Signalling ,Neoplasms ,Humans ,Protein kinase A ,Copper ,Cell Proliferation ,Signal Transduction - Abstract
Copper is an essential nutrient whose redox properties make it both beneficial and toxic to the cell. Recent progress in studying transition metal signalling has forged new links between researchers of different disciplines that can help translate basic research in the chemistry and biology of copper into clinical therapies and diagnostics to exploit copper-dependent disease vulnerabilities. This concept is particularly relevant in cancer, as tumour growth and metastasis have a heightened requirement for this metal nutrient. Indeed, the traditional view of copper as solely an active site metabolic cofactor has been challenged by emerging evidence that copper is also a dynamic signalling metal and metalloallosteric regulator, such as for copper-dependent phosphodiesterase 3B (PDE3B) in lipolysis, mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 in cell growth and proliferation and the kinases ULK1 and ULK2 in autophagy. In this Perspective, we summarize our current understanding of the connection between copper and cancer and explore how challenges in the field could be addressed by using the framework of cuproplasia, which is defined as regulated copper-dependent cell proliferation and is a representative example of a broad range of metalloplasias. Cuproplasia is linked to a diverse array of cellular processes, including mitochondrial respiration, antioxidant defence, redox signalling, kinase signalling, autophagy and protein quality control. Identifying and characterizing new modes of copper-dependent signalling offers translational opportunities that leverage disease vulnerabilities to this metal nutrient.
- Published
- 2021
48. An organogold compound as potential antimicrobial agent against drug resistant bacteria: Initial mechanistic insights
- Author
-
Angela Casini, Dorenda Oosterhuis, Dirk-Jan Scheffers, Riccardo Bonsignore, Peter Olinga, Parichita Chakraborty, Molecular Microbiology, Pharmaceutical Technology and Biopharmacy, Chakraborty P., Oosterhuis D., Bonsignore R., Casini A., Olinga P., and Scheffers D.-J.
- Subjects
Cell Survival ,medicine.drug_class ,Antibiotics ,organometallic drugs ,mode of action ,Microbial Sensitivity Tests ,Gram-Positive Bacteria ,medicine.disease_cause ,Biochemistry ,drug resistant bacteria ,Mice ,Structure-Activity Relationship ,Drug Discovery ,gold compounds ,medicine ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,Mode of action ,Pharmacology ,Full Paper ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Pathogenic bacteria ,Full Papers ,biology.organism_classification ,Antimicrobial ,Anti-Bacterial Agents ,Mechanism of action ,Molecular Medicine ,medicine.symptom ,Antibacterial activity ,Organogold Compounds ,Bacteria ,Ex vivo - Abstract
The rise of antimicrobial resistance has necessitated novel strategies to efficiently combat pathogenic bacteria. Metal‐based compounds have been proven as a possible alternative to classical organic drugs. Here, we have assessed the antibacterial activity of seven gold complexes of different families. One compound, a cyclometalated Au(III) C^N complex, showed activity against Gram‐positive bacteria, including multi‐drug resistant clinical strains. The mechanism of action of this compound was studied in Bacillus subtilis. Overall, the studies point towards a complex mode of antibacterial action, which does not include induction of oxidative stress or cell membrane damage. A number of genes related to metal transport and homeostasis were upregulated upon short treatment of the cells with gold compound. Toxicity tests conducted on precision‐cut mouse tissue slices ex vivo revealed that the organogold compound is poorly toxic to mouse liver and kidney tissues, and may thus, be treated as an antibacterial drug candidate., Genetic‐level effects: We report the antibacterial effects of a gold(III) organometallic compound against Gram‐positive bacteria and the evaluation of its toxicity in healthy tissues in a mouse model ex vivo. The compound's mechanisms of action, elucidated by various assays in B. subtilis, do not include the induction of oxidative stress or bacterial cell membrane damage, but instead involve the alterations of genes related to metal transport and homeostasis, amongst others.
- Published
- 2021
49. Frontispiece: Host–Guest Interactions in a Metal–Organic Framework Isoreticular Series for Molecular Photocatalytic CO 2 Reduction
- Author
-
Christopher Thomas, Roland A. Fischer, Michael Schuster, Julien Warnan, Alexander Urstoeger, Angela Casini, Philip M. Stanley, Natalia B. Shustova, Bernhard Rieger, and Johanna Haimerl
- Subjects
Reduction (complexity) ,Chemical engineering ,Chemistry ,Photocatalysis ,Metal-organic framework ,General Chemistry ,Hybrid material ,Host (network) ,Catalysis - Published
- 2021
50. Frontispiz: Wirt‐Gast‐Wechselwirkungen in einer Serie isoretikulärer Metall‐organischer Gerüststrukturen für molekulare photokatalytische CO 2 ‐Reduktion
- Author
-
Philip M. Stanley, Johanna Haimerl, Christopher Thomas, Alexander Urstoeger, Michael Schuster, Natalia B. Shustova, Angela Casini, Bernhard Rieger, Julien Warnan, and Roland A. Fischer
- Subjects
General Medicine - Published
- 2021
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.