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Special Issue "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: 15 July 2021.

Special Issue Editors

Prof. Dr. Antonello Merlino
E-Mail Website
Guest Editor
Department of Chemical Sciences, University of Naples Federico II, Complesso Universitario di Monte Sant'Angelo, Via Cintia, Napoli, Italy
Interests: protein-metal based drug adducts; X-Ray crystallography; protein metalation; protein-ligand interactions
Special Issues and Collections in MDPI journals
Dr. Giarita Ferraro
E-Mail Website
Guest Editor
Department of Chemistry “Ugo Schiff”, University of Florence, Sesto Fiorentino, Italy

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

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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

Published Papers (6 papers)

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Research

Open AccessArticle
Nerve Growth Factor Peptides Bind Copper(II) with High Affinity: A Thermodynamic Approach to Unveil Overlooked Neurotrophin Roles
Int. J. Mol. Sci. 2021, 22(10), 5085; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105085 - 11 May 2021
Viewed by 201
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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Open AccessArticle
FeIII, CuII and ZnII Complexes of the Rigid 9-Oxido-phenalenone Ligand—Spectroscopy, Electrochemistry, and Cytotoxic Properties
Int. J. Mol. Sci. 2021, 22(8), 3976; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083976 - 12 Apr 2021
Viewed by 334
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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Open AccessArticle
The Affinity of Carboplatin to B-Vitamins and Nucleobases
Int. J. Mol. Sci. 2021, 22(7), 3634; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073634 - 31 Mar 2021
Viewed by 311
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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Open AccessArticle
A Comparative Study of the Effects of Platinum (II) Complexes on β-Amyloid Aggregation: Potential Neurodrug Applications
Int. J. Mol. Sci. 2021, 22(6), 3015; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063015 - 16 Mar 2021
Viewed by 325
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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Open AccessArticle
Arsenoplatin-Ferritin Nanocage: Structure and Cytotoxicity
Int. J. Mol. Sci. 2021, 22(4), 1874; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041874 - 13 Feb 2021
Cited by 1 | Viewed by 485
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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Open AccessArticle
Unusual Structural Features in the Adduct of Dirhodium Tetraacetate with Lysozyme
Int. J. Mol. Sci. 2021, 22(3), 1496; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031496 - 02 Feb 2021
Viewed by 536
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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