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Pharmaceutics
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Metallodrugs: Investigation of the Mechanism of Action and Advanced Delivery...
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Metallodrugs: Investigation of the Mechanism of Action and Advanced Delivery Systems at Molecular Level

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 4263

Special Issue Editors

Dr. Flora Cozzolino

E-Mail Website
Guest Editor
Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
Interests: biomolecular mass spectrometry; structural characterization of peptides and proteins; post-translational modifications; epitope mapping; amyloidosis; protein-drugs interaction; proteomics; native mass spectrometry
Dr. Ilaria Iacobucci

E-Mail Website
Guest Editor
Laboratoire d’Innovation Moléculaire et Applications (LIMA), University of Strasbourg, Strasbourg, France
Interests: biomolecular mass spectrometry; protein-drugs interaction; proteomics; amyloidosis; biomolecule-metallodrug interaction; anticancer metallodrugs; Pt-based compounds; native mass spectrometry

Special Issue Information

Dear Colleagues,

Medicinal inorganic chemistry is a flourishing pharmaceutical research field because of the promising capability of metallodrugs to be used for the treatment of several sporadic and chronic diseases. Even if metal-based compounds have been used since ancient times as antibacterial substances, their applications are increasingly being studied since cisplatin has been discovered as an anticancer molecule, opening new perspectives in the field. The potential of metallodrugs in the treatment of neurodegenerative pathologies and, in very recent times, proposed as SARS-CoV-2 antiviral agents, still underlines how metal complexes can be considered as inexhaustible arrows to our bow in the potential treatment of diseases. This is the reason why the research for the understanding of metallodrugs’ mechanism of action(s) has a pivotal role in their advances as pharmaceutical agents. In addition, the development of new efficient drug delivery systems is crucial to let them reach their molecular target(s). This Special Issue aims to collect studies in the medicinal inorganic chemistry field focusing on the exploring of metallodrugs mechanisms of action and biological activities, as well as novel strategies for improving their delivery to the molecular target. In this Special Issue, original research articles and reviews are welcome.

We look forward to receiving your contributions.

Dr. Flora Cozzolino
Dr. Ilaria Iacobucci
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 submissions that pass pre-check are 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. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • metallodrugs
  • drug–biomolecule interaction
  • metal complexes
  • anticancer delivery systems
  • anti-aggregation molecules
  • anti-viral metallodrugs
  • metal-based drugs mechanisms of action

Published Papers (3 papers)

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Research

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18 pages, 7915 KiB  
Article
Zinc(II)-Sterol Hydrazone Complex as a Potent Anti-Leishmania Agent: Synthesis, Characterization, and Insight into Its Mechanism of Antiparasitic Action
by Gonzalo Visbal, Rodrigo M. S. Justo, Gabrielle dos Santos da Silva e Miranda, Sara Teixeira de Macedo Silva, Wanderley de Souza, Juliany Cola Fernandes Rodrigues and Maribel Navarro
Pharmaceutics 2023, 15(4), 1113; https://doi.org/10.3390/pharmaceutics15041113 - 31 Mar 2023
Cited by 1 | Viewed by 1396
Abstract
Searching for new alternatives for treating leishmaniasis, we present the synthesis, characterization, and biological evaluation against Leishmania amazonensis of the new ZnCl2(H3)2 complex. H3 is 22-hydrazone-imidazoline-2-yl-chol-5-ene-3β-ol, a well-known bioactive molecule functioning as a sterol Δ24-sterol methyl [...] Read more.
Searching for new alternatives for treating leishmaniasis, we present the synthesis, characterization, and biological evaluation against Leishmania amazonensis of the new ZnCl2(H3)2 complex. H3 is 22-hydrazone-imidazoline-2-yl-chol-5-ene-3β-ol, a well-known bioactive molecule functioning as a sterol Δ24-sterol methyl transferase (24-SMT) inhibitor. The ZnCl2(H3)2 complex was characterized by infrared, UV-vis, molar conductance measurements, elemental analysis, mass spectrometry, and NMR experiments. The biological results showed that the free ligand H3 and ZnCl2(H3)2 significantly inhibited the growth of promastigotes and intracellular amastigotes. The IC50 values found for H3 and ZnCl2(H3)2 were 5.2 µM and 2.5 µM for promastigotes, and 543 nM and 32 nM for intracellular amastigotes, respectively. Thus, the ZnCl2(H3)2 complex proved to be seventeen times more potent than the free ligand H3 against the intracellular amastigote, the clinically relevant stage. Furthermore, cytotoxicity assays and determination of selectivity index (SI) revealed that ZnCl2(H3)2 (CC50 = 5 μΜ, SI = 156) is more selective than H3 (CC50 = 10 μΜ, SI = 20). Furthermore, as H3 is a specific inhibitor of the 24-SMT, free sterol analysis was performed. The results showed that H3 was not only able to induce depletion of endogenous parasite sterols (episterol and 5-dehydroepisterol) and their replacement by 24-desalkyl sterols (cholesta-5,7,24-trien-3β-ol and cholesta-7,24-dien-3β-ol) but also its zinc derivative resulting in a loss of cell viability. Using electron microscopy, studies on the fine ultrastructure of the parasites showed significant differences between the control cells and parasites treated with H3 and ZnCl2(H3)2. The inhibitors induced membrane wrinkle, mitochondrial injury, and abnormal chromatin condensation changes that are more intense in the cells treated with ZnCl2(H3)2. Full article
(This article belongs to the Special Issue Metallodrugs: Investigation of the Mechanism of Action and Advanced Delivery Systems at Molecular Level)
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13 pages, 2357 KiB  
Article
Auranofin Targeting the NDM-1 Beta-Lactamase: Computational Insights into the Electronic Configuration and Quasi-Tetrahedral Coordination of Gold Ions
by Iogann Tolbatov and Alessandro Marrone
Pharmaceutics 2023, 15(3), 985; https://doi.org/10.3390/pharmaceutics15030985 - 18 Mar 2023
Cited by 2 | Viewed by 1208
Abstract
Recently, the well-characterized metallodrug auranofin has been demonstrated to restore the penicillin and cephalosporin sensitivity in resistant bacterial strains via the inhibition of the NDM-1 beta-lactamase, which is operated via the Zn/Au substitution in its bimetallic core. The resulting unusual tetrahedral coordination of [...] Read more.
Recently, the well-characterized metallodrug auranofin has been demonstrated to restore the penicillin and cephalosporin sensitivity in resistant bacterial strains via the inhibition of the NDM-1 beta-lactamase, which is operated via the Zn/Au substitution in its bimetallic core. The resulting unusual tetrahedral coordination of the two ions was investigated via the density functional theory calculations. By assessing several charge and multiplicity schemes, coupled with on/off constraining the positions of the coordinating residues, it was demonstrated that the experimental X-ray structure of the gold-bound NDM-1 is consistent with either Au(I)-Au(I) or Au(II)-Au(II) bimetallic moieties. The presented results suggest that the most probable mechanism for the auranofin-based Zn/Au exchange in NDM-1 includes the early formation of the Au(I)-Au(I) system, superseded by oxidation yielding the Au(II)-Au(II) species bearing the highest resemblance to the X-ray structure. Full article
(This article belongs to the Special Issue Metallodrugs: Investigation of the Mechanism of Action and Advanced Delivery Systems at Molecular Level)
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Review

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17 pages, 1790 KiB  
Review
From the Discovery of Targets to Delivery Systems: How to Decipher and Improve the Metallodrugs’ Actions at a Molecular Level
by Ilaria Iacobucci, Sara La Manna, Irene Cipollone, Vittoria Monaco, Luisa Canè and Flora Cozzolino
Pharmaceutics 2023, 15(7), 1997; https://doi.org/10.3390/pharmaceutics15071997 - 21 Jul 2023
Cited by 2 | Viewed by 1153
Abstract
Metals are indispensable for the life of all organisms, and their dysregulation leads to various disorders due to the disruption of their homeostasis. Nowadays, various transition metals are used in pharmaceutical products as diagnostic and therapeutic agents because their electronic structure allows them [...] Read more.
Metals are indispensable for the life of all organisms, and their dysregulation leads to various disorders due to the disruption of their homeostasis. Nowadays, various transition metals are used in pharmaceutical products as diagnostic and therapeutic agents because their electronic structure allows them to adjust the properties of molecules differently from organic molecules. Therefore, interest in the study of metal–drug complexes from different aspects has been aroused, and numerous approaches have been developed to characterize, activate, deliver, and clarify molecular mechanisms. The integration of these different approaches, ranging from chemoproteomics to nanoparticle systems and various activation strategies, enables the understanding of the cellular responses to metal drugs, which may form the basis for the development of new drugs and/or the modification of currently used drugs. The purpose of this review is to briefly summarize the recent advances in this field by describing the technological platforms and their potential applications for identifying protein targets for discovering the mechanisms of action of metallodrugs and improving their efficiency during delivery. Full article
(This article belongs to the Special Issue Metallodrugs: Investigation of the Mechanism of Action and Advanced Delivery Systems at Molecular Level)
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