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Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 27791

Special Issue Editors

Department of Chemical Sciences, University of Naples Federico II (Complesso Universitario di Monte Sant'Angelo), Via Cintia, 80126 Napoli, Italy
Interests: protein-metal based drug adducts; X-Ray crystallography; protein metalation; protein-ligand interactions
Special Issues, Collections and Topics in MDPI journals
Department of Chemistry “Ugo Schiff”, University of Florence, 50019 Sesto Fiorentino, Italy
Interests: metal-based drug; protein metalation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the serendipitous discovery of the cytotoxic activity of cisplatin at the end of the 1960s, Pt- and non-Pt-based compounds have been extensively studied as potential anticancer agents. Metal compounds also play an important role in clinics as antimicrobial, antiviral or antiarthritic agents. A deep knowledge of their mode of action and of their biological targets may help in the design of new molecules with improved biological activities and limited side effects.

This Special Issue of International Journal of Molecular Science on “Metallodrugs: mechanisms of action, molecular targets and biological activity” aims to collect original contributions, letters or review articles describing recent advances in this field.

Topics include, but are not limited to, the synthesis and characterization, including structures and applications, of novel metal compounds with biological activities, insights into stability and reactivity of these compounds, insights into the mechanism of action, potential targets, and biological activity of metallodrugs. The Issue will also collect articles describing the interaction of metallodrugs with biological macromolecules, based on experimental techniques (NMR, X-ray crystallography, mass spectrometry etc.) or using computational approaches.

Prof. Dr. Antonello Merlino
Dr. Giarita Ferraro
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Metal-based drugs
  • Protein metalation
  • Coordination chemistry
  • Metal binding sites
  • Organometallic compounds

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Published Papers (12 papers)

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Editorial

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5 pages, 717 KiB  
Editorial
Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity
by Giarita Ferraro and Antonello Merlino
Int. J. Mol. Sci. 2022, 23(7), 3504; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073504 - 23 Mar 2022
Cited by 5 | Viewed by 1596
Abstract
The research interest in the field of inorganic medicinal chemistry had a large increase after the serendipitous discovery of the cytotoxic activity of cisplatin by Rosenberg at the end of 1960s [...] Full article
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Research

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18 pages, 8664 KiB  
Article
Cellular and Molecular Targets of Nucleotide-Tagged Trithiolato-Bridged Arene Ruthenium Complexes in the Protozoan Parasites Toxoplasma gondii and Trypanosoma brucei
by Nicoleta Anghel, Joachim Müller, Mauro Serricchio, Jennifer Jelk, Peter Bütikofer, Ghalia Boubaker, Dennis Imhof, Jessica Ramseier, Oksana Desiatkina, Emilia Păunescu, Sophie Braga-Lagache, Manfred Heller, Julien Furrer and Andrew Hemphill
Int. J. Mol. Sci. 2021, 22(19), 10787; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910787 - 05 Oct 2021
Cited by 12 | Viewed by 2159
Abstract
Toxoplasma gondii is an apicomplexan parasite that infects and proliferates within many different types of host cells and infects virtually all warm-blooded animals and humans. Trypanosoma brucei is an extracellular kinetoplastid that causes human African trypanosomiasis and Nagana disease in cattle, primarily in [...] Read more.
Toxoplasma gondii is an apicomplexan parasite that infects and proliferates within many different types of host cells and infects virtually all warm-blooded animals and humans. Trypanosoma brucei is an extracellular kinetoplastid that causes human African trypanosomiasis and Nagana disease in cattle, primarily in rural sub-Saharan Africa. Current treatments against both parasites have limitations, e.g., suboptimal efficacy and adverse side effects. Here, we investigate the potential cellular and molecular targets of a trithiolato-bridged arene ruthenium complex conjugated to 9-(2-hydroxyethyl)-adenine (1), which inhibits both parasites with IC50s below 10−7 M. Proteins that bind to 1 were identified using differential affinity chromatography (DAC) followed by shotgun-mass spectrometry. A trithiolato-bridged ruthenium complex decorated with hypoxanthine (2) and 2-hydroxyethyl-adenine (3) were included as controls. Transmission electron microscopy (TEM) revealed distinct ultrastructural modifications in the mitochondrion induced by (1) but not by (2) and (3) in both species. DAC revealed 128 proteins in T. gondii and 46 proteins in T. brucei specifically binding to 1 but not 2 or 3. In T. gondii, the most abundant was a protein with unknown function annotated as YOU2. This protein is a homolog to the human mitochondrial inner membrane translocase subunit Tim10. In T. brucei, the most abundant proteins binding specifically to 1 were mitochondrial ATP-synthase subunits. Exposure of T. brucei bloodstream forms to 1 resulted in rapid breakdown of the ATP-synthase complex. Moreover, both datasets contained proteins involved in key steps of metabolism and nucleic acid binding proteins. Full article
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15 pages, 2320 KiB  
Article
Heterogeneity of Response to Iron-Based Metallodrugs in Glioblastoma Is Associated with Differences in Chemical Structures and Driven by FAS Expression Dynamics and Transcriptomic Subtypes
by Anne Vessières, Emie Quissac, Nolwenn Lemaire, Agusti Alentorn, Patrycja Domeracka, Pascal Pigeon, Marc Sanson, Ahmed Idbaih and Maïté Verreault
Int. J. Mol. Sci. 2021, 22(19), 10404; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910404 - 27 Sep 2021
Cited by 11 | Viewed by 2151
Abstract
Glioblastoma (GBM) is the most frequent and deadliest primary brain cancer in adults, justifying the search for new treatments. Some members of the iron-based ferrocifen family have demonstrated a high cytotoxic effect on various cancer cell lines via innovative mechanisms of action. Here, [...] Read more.
Glioblastoma (GBM) is the most frequent and deadliest primary brain cancer in adults, justifying the search for new treatments. Some members of the iron-based ferrocifen family have demonstrated a high cytotoxic effect on various cancer cell lines via innovative mechanisms of action. Here, we evaluated the antiproliferative activity by wst-1 assay of six ferrocifens in 15 molecularly diverse GBM patient-derived cell lines (PDCLs). In five out of six compounds, the half maximal inhibitory concentration (IC50) values varied significantly (10 nM < IC50 < 29.8 µM) while the remaining one (the tamoxifen-like complex) was highly cytotoxic against all PDCLs (mean IC50 = 1.28 µM). The pattern of response was comparable for the four ferrocifens bearing at least one phenol group and differed widely from those of the tamoxifen-like complex and the complex with no phenol group. An RNA sequencing differential analysis showed that response to the diphenol ferrocifen relied on the activation of the Death Receptor signaling pathway and the modulation of FAS expression. Response to this complex was greater in PDCLs from the Mesenchymal or Proneural transcriptomic subtypes compared to the ones from the Classical subtype. These results provide new information on the mechanisms of action of ferrocifens and highlight a broader diversity of behavior than previously suspected among members of this family. They also support the case for a molecular-based personalized approach to future use of ferrocifens in the treatment of GBM. Full article
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26 pages, 3689 KiB  
Article
Peptides Derived from Angiogenin Regulate Cellular Copper Uptake
by Giovanni Tabbì, Lorena Maria Cucci, Calogero Pinzino, Alessia Munzone, Tiziano Marzo, Silvia Pizzanelli, Cristina Satriano, Antonio Magrì and Diego La Mendola
Int. J. Mol. Sci. 2021, 22(17), 9530; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179530 - 02 Sep 2021
Cited by 3 | Viewed by 1739
Abstract
The angiogenin protein (ANG) is one of the most potent endogenous angiogenic factors. In this work we characterized by means of potentiometric, spectroscopic and voltammetric techniques, the copper complex species formed with peptide fragments derived from the N-terminal domain of the protein, encompassing [...] Read more.
The angiogenin protein (ANG) is one of the most potent endogenous angiogenic factors. In this work we characterized by means of potentiometric, spectroscopic and voltammetric techniques, the copper complex species formed with peptide fragments derived from the N-terminal domain of the protein, encompassing the sequence 1-17 and having free amino, Ang1-17, or acetylated N-terminus group, AcAng1-17, so to explore the role of amino group in metal binding and cellular copper uptake. The obtained data show that amino group is the main copper anchoring site for Ang1-17. The affinity constant values, metal coordination geometry and complexes redox-potentials strongly depend, for both peptides, on the number of copper equivalents added. Confocal laser scanning microscope analysis on neuroblastoma cells showed that in the presence of one equivalent of copper ion, the free amino Ang1-17 increases cellular copper uptake while the acetylated AcAng1-17 strongly decreases the intracellular metal level. The activity of peptides was also compared to that of the protein normally present in the plasma (wtANG) as well as to the recombinant form (rANG) most commonly used in literature experiments. The two protein isoforms bind copper ions but with a different coordination environment. Confocal laser scanning microscope data showed that the wtANG induces a strong increase in intracellular copper compared to control while the rANG decreases the copper signal inside cells. These data demonstrate the relevance of copper complexes’ geometry to modulate peptides’ activity and show that wtANG, normally present in the plasma, can affect cellular copper uptake. Full article
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20 pages, 5054 KiB  
Article
Square-Planar vs. Trigonal Bipyramidal Geometry in Pt(II) Complexes Containing Triazole-Based Glucose Ligands as Potential Anticancer Agents
by Alfonso Annunziata, Davide Liberti, Emiliano Bedini, Maria Elena Cucciolito, Domenico Loreto, Daria Maria Monti, Antonello Merlino and Francesco Ruffo
Int. J. Mol. Sci. 2021, 22(16), 8704; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168704 - 13 Aug 2021
Cited by 7 | Viewed by 2286
Abstract
This article describes the synthesis, characterization, and biological activity of novel square-planar cationic platinum(II) complexes containing glucoconjugated triazole ligands and a comparison with the results obtained from the corresponding five-coordinate complexes bearing the same triazole ligands. Stability in solution, reactivity with DNA and [...] Read more.
This article describes the synthesis, characterization, and biological activity of novel square-planar cationic platinum(II) complexes containing glucoconjugated triazole ligands and a comparison with the results obtained from the corresponding five-coordinate complexes bearing the same triazole ligands. Stability in solution, reactivity with DNA and small molecules of the new compounds were evaluated by NMR, fluorescence, and UV–vis absorption spectroscopy, together with their cytotoxic action against pairs of immortalized and tumorigenic cell lines. The results show that the square-planar species exhibit greater stability than the corresponding five-coordinate ones. Furthermore, although the square-planar complexes are less cytotoxic than the latter ones, they exhibit a certain selectivity. These results simultaneously demonstrate that overall stability is a fundamental prerequisite for preserving the performance of the agents and that coordinative saturation constitutes a point in favor of their biological action. Full article
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18 pages, 2643 KiB  
Article
A Comparative Analysis of the In Vitro Anticancer Activity of Iridium(III) {η5-C5Me4R} Complexes with Variable R Groups
by Alice De Palo, Dijana Draca, Maria Grazia Murrali, Stefano Zacchini, Guido Pampaloni, Sanja Mijatovic, Danijela Maksimovic-Ivanic and Fabio Marchetti
Int. J. Mol. Sci. 2021, 22(14), 7422; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147422 - 10 Jul 2021
Cited by 4 | Viewed by 2488
Abstract
Piano-stool iridium complexes based on the pentamethylcyclopentadienyl ligand (Cp*) have been intensively investigated as anticancer drug candidates and hold much promise in this setting. A systematic study aimed at outlining the effect of Cp* mono-derivatization on the antiproliferative activity is presented here. Thus, [...] Read more.
Piano-stool iridium complexes based on the pentamethylcyclopentadienyl ligand (Cp*) have been intensively investigated as anticancer drug candidates and hold much promise in this setting. A systematic study aimed at outlining the effect of Cp* mono-derivatization on the antiproliferative activity is presented here. Thus, the dinuclear complexes [Ir(η5-C5Me4R)Cl(μ-Cl)]2 (R = Me, 1a; R = H, 1b; R = Pr, 1c; R = 4-C6H4F, 1d; R = 4-C6H4OH, 1e), their 2-phenylpyridyl mononuclear derivatives [Ir(η5-C5Me4R)(kN,kCPhPy)Cl] (2a–d), and the dimethylsulfoxide complex [Ir{η5-C5Me4(4-C6H4OH)}Cl2S-Me2S=O)] (3) were synthesized, structurally characterized, and assessed for their cytotoxicity towards a panel of six human and rodent cancer cell lines (mouse melanoma, B16; rat glioma, C6; breast adenocarcinoma, MCF-7; colorectal carcinoma, SW620 and HCT116; ovarian carcinoma, A2780) and one primary, human fetal lung fibroblast cell line (MRC5). Complexes 2b (R = H) and 2d (4-C6H4F) emerged as the most active ones and were selected for further investigation. They did not affect the viability of primary mouse peritoneal cells, and their tumoricidal action arises from the combined influence on cellular proliferation, apoptosis and senescence. The latter is triggered by mitochondrial failure and production of reactive oxygen and nitrogen species. Full article
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15 pages, 810 KiB  
Article
Nerve Growth Factor Peptides Bind Copper(II) with High Affinity: A Thermodynamic Approach to Unveil Overlooked Neurotrophin Roles
by Antonio Magrì, Diego La Mendola and Enrico Rizzarelli
Int. J. Mol. Sci. 2021, 22(10), 5085; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105085 - 11 May 2021
Cited by 4 | Viewed by 2183
Abstract
Nerve growth factor (NGF) is a protein essential to neurons survival, which interacts with its receptor as a non-covalent dimer. Peptides belonging to NGF N-terminal domain are able to mimic the activity of the whole protein. Such activity is affected by the presence [...] Read more.
Nerve growth factor (NGF) is a protein essential to neurons survival, which interacts with its receptor as a non-covalent dimer. Peptides belonging to NGF N-terminal domain are able to mimic the activity of the whole protein. Such activity is affected by the presence of copper ions. The metal is released in the synaptic cleft where proteins, not yet identified, may bind and transfer to human copper transporter 1 (hCtr1), for copper uptake in neurons. The measurements of the stability constants of copper complexes formed by amyloid beta and hCtr1 peptide fragments suggest that beta-amyloid (Aβ) can perform this task. In this work, the stability constant values of copper complex species formed with the dimeric form of N-terminal domain, sequence 1–15 of the protein, were determined by means of potentiometric measurements. At physiological pH, NGF peptides bind one equivalent of copper ion with higher affinity of Aβ and lower than hCtr1 peptide fragments. Therefore, in the synaptic cleft, NGF may act as a potential copper chelating molecule, ionophore or chaperone for hCtr1 for metal uptake. Copper dyshomeostasis and mild acidic environment may modify the balance between metal, NGF, and Aβ, with consequences on the metal cellular uptake and therefore be among causes of the Alzheimer’s disease onset. Full article
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18 pages, 2382 KiB  
Article
FeIII, CuII and ZnII Complexes of the Rigid 9-Oxido-phenalenone Ligand—Spectroscopy, Electrochemistry, and Cytotoxic Properties
by Katharina Butsch, Alexander Haseloer, Simon Schmitz, Ingo Ott, Julia Schur and Axel Klein
Int. J. Mol. Sci. 2021, 22(8), 3976; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083976 - 12 Apr 2021
Cited by 1 | Viewed by 2479
Abstract
The three complexes [Fe(opo)3], [Cu(opo)2], and [Zn(opo)2] containing the non-innocent anionic ligand opo (opo = 9-oxido-phenalenone, Hopo = 9-hydroxyphenalonone) were synthesised from the corresponding acetylacetonates. [Zn(opo)2] was characterised using 1H nuclear magnetic [...] Read more.
The three complexes [Fe(opo)3], [Cu(opo)2], and [Zn(opo)2] containing the non-innocent anionic ligand opo (opo = 9-oxido-phenalenone, Hopo = 9-hydroxyphenalonone) were synthesised from the corresponding acetylacetonates. [Zn(opo)2] was characterised using 1H nuclear magnetic resonance (NMR) spectroscopy, the paramagnetic [Fe(opo)3] and [Cu(opo)2] by electron paramagnetic resonance (EPR) spectroscopy. While the EPR spectra of [Cu(opo)2] and [Cu(acac)2] in dimethylformamide (DMF) solution are very similar, a rather narrow spectrum was observed for [Fe(opo)3] in tetrahydrofuran (THF) solution in contrast to the very broad spectrum of [Fe(acac)3] in THF (Hacac = acetylacetone, 2,4-pentanedione; acac = acetylacetonate). The narrow, completely isotropic signal of [Fe(opo)3] disagrees with a metal-centred S = 5/2 spin system that is observed in the solid state. We assume spin-delocalisation to the opo ligand in the sense of an opo to FeIII electron transfer. All compounds show several electrochemical opo-centred reduction waves in the range of −1 to −3 V vs. the ferrocene/ferrocenium couple. However, for CuII and FeIII the very first one-electron reductions are metal-centred. Electronic absorption in the UV to vis range are due to π–π* transitions in the opo core, giving Hopo and [Zn(opo)2] a yellow to orange colour. The structured bands ranging from 400 to 500 for all compounds are assigned to the lowest energy π−π* transitions. They show markedly higher intensities and slight shifts for the CuII (brown) and FeIII (red) complexes and we assume admixing metal contributions (MLCT for CuII, LMCT for FeIII). For both complexes long-wavelength absorptions assignable to d–d transitions were detected. Detailed spectroelectrochemical experiments confirm both the electrochemical and the optical assignments. Hopo and the complexes [Cu(opo)2], [Zn(opo)2], and [Fe(opo)3] show antiproliferative activities against HT-29 (colon cancer) and MCF-7 (breast cancer) cell lines in the range of a few µM, comparable to cisplatin under the same conditions. Full article
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11 pages, 15432 KiB  
Article
The Affinity of Carboplatin to B-Vitamins and Nucleobases
by Beata Szefler, Przemysław Czeleń and Przemysław Krawczyk
Int. J. Mol. Sci. 2021, 22(7), 3634; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073634 - 31 Mar 2021
Cited by 9 | Viewed by 2253
Abstract
Platinum compounds have found wide application in the treatment of various types of cancer and carboplatin is one of the main platinum-based drugs used as antitumor agents. The anticancer activity of carboplatin arises from interacting with DNA and inducing programmed cell death. However, [...] Read more.
Platinum compounds have found wide application in the treatment of various types of cancer and carboplatin is one of the main platinum-based drugs used as antitumor agents. The anticancer activity of carboplatin arises from interacting with DNA and inducing programmed cell death. However, such interactions may occur with other chemical compounds, such as vitamins containing aromatic rings with lone-pair orbitals, which reduces the anti-cancer effect of carboplatin. The most important aspect of the conducted research was related to the evaluation of carboplatin affinity to vitamins from the B group and the potential impact of such interactions on the reduction of therapeutic capabilities of carboplatin in anticancer therapy. Realized computations, including estimation of Gibbs Free Energies, allowed for the identification of the most reactive molecule, namely vitamin B6 (pyridoxal phosphate). In this case, the computational estimations indicating carboplatin reactivity were confirmed by spectrophotometric measurements. Full article
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13 pages, 2029 KiB  
Article
A Comparative Study of the Effects of Platinum (II) Complexes on β-Amyloid Aggregation: Potential Neurodrug Applications
by Sara La Manna, Daniele Florio, Ilaria Iacobucci, Fabiana Napolitano, Ilaria De Benedictis, Anna Maria Malfitano, Maria Monti, Mauro Ravera, Elisabetta Gabano and Daniela Marasco
Int. J. Mol. Sci. 2021, 22(6), 3015; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063015 - 16 Mar 2021
Cited by 21 | Viewed by 2198
Abstract
Herein the effects of three platinum complexes, namely (SP-4-2)-(2,2′-bipyridine)dichloridoplatinum(II), Pt-bpy, (SP-4-2)-dichlorido(1,10-phenanthroline) platinum(II), Pt-phen, and (SP-4-2)-chlorido(2,2′:6′,2′′-terpyridine)platinum(II) chloride, Pt-terpy, on the aggregation of an amyloid model system derived from the C-terminal domain of Aβ peptide (Aβ21–40) were [...] Read more.
Herein the effects of three platinum complexes, namely (SP-4-2)-(2,2′-bipyridine)dichloridoplatinum(II), Pt-bpy, (SP-4-2)-dichlorido(1,10-phenanthroline) platinum(II), Pt-phen, and (SP-4-2)-chlorido(2,2′:6′,2′′-terpyridine)platinum(II) chloride, Pt-terpy, on the aggregation of an amyloid model system derived from the C-terminal domain of Aβ peptide (Aβ21–40) were investigated. Thioflavin T (ThT) binding assays revealed the ability of Pt(II) compounds to repress amyloid aggregation in a dose-dependent way, whereas the ability of Aβ21–40 peptide to interfere with ligand field of metal complexes was analyzed through UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. Spectroscopic data provided micromolar EC50 values and allowed to assess that the observed inhibition of amyloid aggregation is due to the formation of adducts between Aβ21–40 peptide and complexes upon the release of labile ligands as chloride and that they can explore different modes of coordination toward Aβ21–40 with respect to the entire Aβ1–40 polypeptide. In addition, conformational studies through circular dichroism (CD) spectroscopy suggested that Pt-terpy induces soluble β-structures of monomeric Aβ21–40, thus limiting self-recognition. Noticeably, Pt-terpy demonstrated the ability to reduce the cytotoxicity of amyloid peptide in human SH-SY5Y neuroblastoma cells. Presented data corroborate the hypothesis to enlarge the application field of already known metal-based agents to neurodegenerative diseases, as potential neurodrugs. Full article
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11 pages, 8731 KiB  
Article
Arsenoplatin-Ferritin Nanocage: Structure and Cytotoxicity
by Giarita Ferraro, Alessandro Pratesi, Damiano Cirri, Paola Imbimbo, Daria Maria Monti, Luigi Messori and Antonello Merlino
Int. J. Mol. Sci. 2021, 22(4), 1874; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041874 - 13 Feb 2021
Cited by 8 | Viewed by 2201
Abstract
Arsenoplatin-1 (AP-1), the prototype of a novel class of metallodrugs containing a PtAs(OH)2 core, was encapsulated within the apoferritin (AFt) nanocage. UV-Vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy measurements confirmed metallodrug encapsulation and allowed us to determine the average amount [...] Read more.
Arsenoplatin-1 (AP-1), the prototype of a novel class of metallodrugs containing a PtAs(OH)2 core, was encapsulated within the apoferritin (AFt) nanocage. UV-Vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy measurements confirmed metallodrug encapsulation and allowed us to determine the average amount of AP-1 trapped inside the cage. The X-ray structure of AP-1-encapsulated AFt was solved at 1.50 Å. Diffraction data revealed that an AP-1 fragment coordinates the side chain of a His residue. The biological activity of AP-1-loaded AFt was comparatively tested on a few representative cancer and non-cancer cell lines. Even though the presence of the cage reduces the overall cytotoxicity of AP-1, it improves its selectivity towards cancer cells. Full article
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16 pages, 5055 KiB  
Article
Unusual Structural Features in the Adduct of Dirhodium Tetraacetate with Lysozyme
by Domenico Loreto, Giarita Ferraro and Antonello Merlino
Int. J. Mol. Sci. 2021, 22(3), 1496; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031496 - 02 Feb 2021
Cited by 20 | Viewed by 2773
Abstract
The structures of the adducts formed upon reaction of the cytotoxic paddlewheel dirhodium complex [Rh2(μ-O2CCH3)4] with the model protein hen egg white lysozyme (HEWL) under different experimental conditions are reported. Results indicate that [Rh2 [...] Read more.
The structures of the adducts formed upon reaction of the cytotoxic paddlewheel dirhodium complex [Rh2(μ-O2CCH3)4] with the model protein hen egg white lysozyme (HEWL) under different experimental conditions are reported. Results indicate that [Rh2(μ-O2CCH3)4] extensively reacts with HEWL:it in part breaks down, at variance with what happens in reactions with other proteins. A Rh center coordinates the side chains of Arg14 and His15. Dimeric Rh–Rh units with Rh–Rh distances between 2.3 and 2.5 Å are bound to the side chains of Asp18, Asp101, Asn93, and Lys96, while a dirhodium unit with a Rh–Rh distance of 3.2–3.4 Å binds the C-terminal carboxylate and the side chain of Lys13 at the interface between two symmetry-related molecules. An additional monometallic fragment binds the side chain of Lys33. These data, which are supported by replicated structural determinations, shed light on the reactivity of dirhodium tetracarboxylates with proteins, providing useful information for the design of new Rh-containing biomaterials with an array of potential applications in the field of catalysis or of medicinal chemistry and valuable insight into the mechanism of action of these potential anticancer agents. Full article
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