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Special Issue "Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity 2.0"

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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 (30 September 2023) | Viewed by 6306

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Prof. Dr. Antonello Merlino

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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
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Dr. Giarita Ferraro

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Department of Chemistry “Ugo Schiff”, University of Florence, 50019 Sesto Fiorentino, Italy
Interests: metal-based drug; protein metalation
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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 aid the design of new molecules with improved biological activities and limited side effects.

This Special Issue of the International Journal of Molecular Science on “Metallodrugs: mechanisms of action, molecular targets and biological activity 2.0” is a continuation of the first volume in 2021 (https://www.mdpi.com/journal/ijms/special_issues/Metallodrugs_Molecular), and 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 of novel metal compounds with biological activities, including structures and applications; insights into the stability and reactivity of these compounds; and insights into the mechanism of action, potential targets, and biological activity of metallodrugs. This Special 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 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. 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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Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity in International Journal of Molecular Sciences (12 articles)

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Open AccessArticle

Novel Silver Complexes Based on Phosphanes and Ester Derivatives of Bis(pyrazol-1-yl)acetate Ligands Targeting TrxR: New Promising Chemotherapeutic Tools Relevant to SCLC Management

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Int. J. Mol. Sci. 2023, 24(4), 4091; https://doi.org/10.3390/ijms24044091 - 17 Feb 2023

Cited by 2 | Viewed by 1146

Abstract

Bis(pyrazol-1-yl)acetic acid (HC(pz)₂COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pz^Me2)₂COOH) were converted into the methyl ester derivatives 1 (L^OMe) and 2 (L^2OMe), respectively, and were used for the preparation of silver(I) complexes 3–5. The Ag(I) complexes were prepared by the reaction of AgNO₃ and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine (PPh₃) with L^OMe and L^2OMe in methanol solution. All Ag(I) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in the in-house human cancer cell line panel containing examples of different solid tumors. Compounds were particularly effective against the highly aggressive and intrinsically resistant human small-cell lung carcinoma (SCLC) cells, either in 2D and 3D cancer cell models. Mechanistic studies revealed their ability to accumulate into cancer cells and to selectively target Thioredoxin (TrxR), thus leading to redox homeostasis unbalance and ultimately inducing cancer cell death through apoptosis. Full article

(This article belongs to the Special Issue Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity 2.0)

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Open AccessArticle

Evaluation of Auranofin Loading within Ferritin Nanocages

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Int. J. Mol. Sci. 2022, 23(22), 14162; https://doi.org/10.3390/ijms232214162 - 16 Nov 2022

Cited by 2 | Viewed by 976

Abstract

Auranofin (AF), a gold(I) compound that is currently used for the treatment of rheumatoid arthritis and is in clinical trials for its promising anticancer activity, was encapsulated within the human H-chain and the horse spleen ferritin nanocages using the alkaline disassembly/reassembly protocol. The aim of the work was to highlight possible differences in their drug loading capacity and efficacy. The drug-loaded ferritins were characterized via UV-vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy to assess AF encapsulation and to define the exact amount of gold atoms trapped in the Ft cavity. The crystal structures allowed us to define the nature of AF interaction with both ferritins and to identify the gold binding sites. Moreover, the biological characterization let us to obtain preliminary information on the cytotoxic effect of AF when bound to the human H-chain. Full article

(This article belongs to the Special Issue Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity 2.0)

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Open AccessArticle

Stabilization of the c-Myc Protein via the Modulation of Threonine 58 and Serine 62 Phosphorylation by the Disulfiram/Copper Complex in Oral Cancer Cells

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Int. J. Mol. Sci. 2022, 23(16), 9137; https://doi.org/10.3390/ijms23169137 - 15 Aug 2022

Cited by 1 | Viewed by 1242

Abstract

MYC has a short half-life that is tightly regulated through phosphorylation and proteasomal degradation. Many studies have claimed that treatment with disulfiram (DSF) with or without copper ions can cause cancer cell death in a reactive oxygen species (ROS)-dependent manner in cancer cells. Our previous study showed that the levels of c-Myc protein and the phosphorylation of threonine 58 (T58) and serine 62 (S62) increased in DSF-Cu-complex-treated oral epidermoid carcinoma Meng-1 (OECM-1) cells. These abovementioned patterns were suppressed by pretreatment with an ROS scavenger, N-acetyl cysteine. The overexpression of c-Myc failed to induce hypoxia-inducible factor 1α protein expression, which was stabilized by the DSF-Cu complex. In this study, we further examined the regulatory mechanism behind the induction of the c-Myc of the DSF-Cu complex in an OECM-1 cell compared with a Smulow–Glickman (SG) human normal gingival epithelial cell. Our data showed that the downregulation of c-Myc truncated nick and p62 and the induction of the ratio of H3P/H3 and p-ERK/ERK might not be involved in the increase in the amount of c-Myc via the DSF/copper complexes in OECM-1 cells. Combined with the inhibitors for various signaling pathways and cycloheximde treatment, the increase in the amount of c-Myc with the DSF/copper complexes might be mediated through the increase in the stabilities of c-Myc (T58) and c-Myc (S62) proteins in OECM-1 cells. In SG cells, only the c-Myc (T58) protein was stabilized by the DSF-Cu (I and II) complexes. Hence, our findings could provide novel regulatory insights into the phosphorylation-dependent stability of c-Myc in DSF/copper-complex-treated oral squamous cell carcinoma. Full article

(This article belongs to the Special Issue Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity 2.0)

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Open AccessArticle

Impact of Polypyridyl Ru Complexes on Angiogenesis—Contribution to Their Antimetastatic Activity

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Int. J. Mol. Sci. 2022, 23(14), 7708; https://doi.org/10.3390/ijms23147708 - 12 Jul 2022

Cited by 2 | Viewed by 1222

Abstract

The use of polypyridyl Ru complexes to inhibit metastasis is a novel approach, and recent studies have shown promising results. We have reported recently that Ru (II) complexes gathering two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and the one being 2,2′-bipyridine (bpy) or its derivative with a 4-[3-(2-nitro-1H-imidazol-1-yl)propyl (bpy-NitroIm) or 5-(4-{4′-methyl-[2,2′-bipyridine]-4-yl}but-1-yn-1-yl)pyridine-2-carbaldehyde semicarbazone (bpy-SC) moieties can alter the metastatic cascade, among others, by modulating cell adhesion properties. In this work, we show further studies of this group of complexes by evaluating their effect on HMEC-1 endothelial cells. While all the tested complexes significantly inhibited the endothelial cell migration, Ru-bpy additionally interrupted the pseudovessels formation. Functional changes in endothelial cells might arise from the impact of the studied compounds on cell elasticity and expression of proteins (vinculin and paxillin) involved in focal adhesions. Furthermore, molecular studies showed that complexes modulate the expression of cell adhesion molecules, which has been suggested to be one of the factors that mediate the activation of angiogenesis. Based on the performed studies, we can conclude that the investigated polypyridyl Ru (II) complexes can deregulate the functionality of endothelial cells which may lead to the inhibition of angiogenesis. Full article

(This article belongs to the Special Issue Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity 2.0)

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Open AccessArticle

Medicinal Hypervalent Tellurium Prodrugs Bearing Different Ligands: A Comparative Study of the Chemical Profiles of AS101 and Its Halido Replaced Analogues

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Int. J. Mol. Sci. 2022, 23(14), 7505; https://doi.org/10.3390/ijms23147505 - 06 Jul 2022

Cited by 3 | Viewed by 1043

Abstract

Ammonium trichloro (dioxoethylene-O,O′) tellurate (AS101) is a potent immunomodulator prodrug that, in recent years, entered various clinical trials and was tested for a variety of potential therapeutic applications. It has been demonstrated that AS101 quickly activates in aqueous milieu, producing TeOCl₃⁻, which likely represents the pharmacologically active species. Here we report on the study of the activation process of AS101 and of two its analogues. After the synthesis and characterization of AS101 and its derivatives, we have carried out a comparative study through a combined experimental and computational analysis. Based on the obtained results, we describe here, for the first time, the detailed reaction that AS101 and its bromido- and iodido-replaced analogues undergo in presence of water, allowing the conversion of the original molecule to the likely true pharmacophore. Interestingly, moving down in the halogens’ group we observed a higher tendency to react, attributable to the ligands’ effect. The chemical and mechanistic implications of these meaningful differences are discussed. Full article

(This article belongs to the Special Issue Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity 2.0)

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