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Special Issue "Metal Based Drugs: Opportunities and Challenges"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (10 July 2017)

Special Issue Editors

Guest Editor
Prof. Dr. Patrick Gamez

ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain
Website | E-Mail
Interests: medicinal inorganic chemistry; bio-inorganic chemistry; amyloid-beta; peptide-based drugs; copper-Reactive oxygen species (ROS); structure-targeted biomolecular recognition; DNA structures; theragnostics; nanoparticles
Guest Editor
Dr. Ana B. Caballero

Departament de Química Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain
Website | E-Mail
Interests: bioinorganic chemistry; Alzheimer's disease; cancer; metal complexes; peptides; nanoparticles; bioactive ligands

Special Issue Information

Dear Colleagues,

Metal-based drugs are used for a wide range of human diseases, beyond their well-known applications in cancer (cisplatin) or rheumatoid arthritis (auranofin). For instance, a number of metal complexes have been developed for the treatment/cure of a variety of disorders such as ulcers, diabetes, inflammatory and cardiovascular diseases, and so on.

The development of drugs based on coordination compounds, i.e., metal complexes, offers the possibility of great structural versatility, compared to purely organic molecules, as they are generated from the combination of different metal ion(s) with distinct ligand(s). The binding of the ligand to the metal ion gives rise to drastic changes in the biological properties of both the organic (ligand) and the inorganic (metal) part. Metal complexes may exert their therapeutic effect through the interaction with cellular organelles, inhibition of enzymes, alteration of the cell membrane, enhanced lipophilicity, cell–cycle arrest, etc.

This Special Issue is aimed at providing a forum for the dissemination of information on the most recent and relevant research in this topical and exciting area of current investigation.

Prof. Dr. Patrick Gamez
Dr. Ana Belén Caballero
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. Molecules 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 1800 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

  • metal-based therapeutic agents
  • contrast agents for Magnetic Resonance Imaging (MRI)
  • radiopharmaceuticals
  • chelation therapy
  • antimicrobials
  • antivirals
  • antiparasitic agents

Published Papers (11 papers)

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Research

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Open AccessCommunication The Anti-Proliferation Activity and Mechanism of Action of K12[V18O42(H2O)]∙6H2O on Breast Cancer Cell Lines
Molecules 2017, 22(9), 1535; doi:10.3390/molecules22091535
Received: 11 July 2017 / Revised: 6 September 2017 / Accepted: 7 September 2017 / Published: 12 September 2017
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Abstract
Polyoxometalates (POMs) are inorganic clusters that possess potential anti-bacterial, anti-viral, and anti-tumor activities. Herein, the in vitro anti-proliferation activities of K12[V18O42(H2O)]∙6H2O (V18) have been investigated on the MCF-7 and MDA-MB-231
[...] Read more.
Polyoxometalates (POMs) are inorganic clusters that possess potential anti-bacterial, anti-viral, and anti-tumor activities. Herein, the in vitro anti-proliferation activities of K12[V18O42(H2O)]∙6H2O (V18) have been investigated on the MCF-7 and MDA-MB-231 cell lines. The results indicated that V18 could inhibit the proliferation of MCF-7 (IC50, 11.95 μM at 48 h) in a dose-dependent manner compared to the positive control, 5-fluorouracil (5-Fu, p < 0.05). The anti-proliferation activity of V18 might be mediated by arrest of the MCF-7 cells in the G2/M phase and induction of apoptosis and necrosis. Moreover, V18 can effectively quench the fluorescence of ctDNA. The binding mode between them may be groove or outside stacking binding. V18 can also effectively quench the intrinsic fluorescence of bovine serum albumin (BSA) and human serum albumin (HSA) via static quenching, and changed the conformation of BSA and HSA. Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
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Open AccessArticle NO-Donor Iron Nitrosyl Complex with N-Ethylthiourea Ligand Exhibits Selective Toxicity to Glioma A172 Cells
Molecules 2017, 22(9), 1426; doi:10.3390/molecules22091426
Received: 10 July 2017 / Accepted: 22 August 2017 / Published: 29 August 2017
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Abstract
We studied effects of NO-donor iron nitrosyl complex with N-ethylthiourea ligand (ETM) on normal or tumor-derived cell lines. ETM was mildly toxic to most cell lines studied except the human glioma cell line A172 that proved to be highly sensitive to the
[...] Read more.
We studied effects of NO-donor iron nitrosyl complex with N-ethylthiourea ligand (ETM) on normal or tumor-derived cell lines. ETM was mildly toxic to most cell lines studied except the human glioma cell line A172 that proved to be highly sensitive to the complex and underwent cell death after ETM exposure. The high susceptibility of A172 cells to ETM was attributed to its NO-donor properties since no toxicity was detected for the N-ethylthiourea ligand. Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
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Open AccessArticle The [Mo6Cl14]2− Cluster is Biologically Secure and Has Anti-Rotavirus Activity In Vitro
Molecules 2017, 22(7), 1108; doi:10.3390/molecules22071108
Received: 9 May 2017 / Revised: 26 June 2017 / Accepted: 29 June 2017 / Published: 5 July 2017
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Abstract
The molybdenum cluster [Mo6Cl14]2− is a fluorescent component with potential for use in cell labelling and pharmacology. Biological safety and antiviral properties of the cluster are as yet unknown. Here, we show the effect of acute exposition of
[...] Read more.
The molybdenum cluster [Mo6Cl14]2− is a fluorescent component with potential for use in cell labelling and pharmacology. Biological safety and antiviral properties of the cluster are as yet unknown. Here, we show the effect of acute exposition of human cells and red blood cells to the molybdenum cluster and its interaction with proteins and antiviral activity in vitro. We measured cell viability of HepG2 and EA.hy926 cell lines exposed to increasing concentrations of the cluster (0.1 to 250 µM), by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Hemolysis and morphological alterations of red blood cells, obtained from healthy donors, exposed to the cluster (10 to 200 µM) at 37 °C were analyzed. Furthermore, quenching of tryptophan residues of albumin was performed. Finally, plaque formation by rotavirus SA11 in MA104 cells treated with the cluster (100 to 300 µM) were analyzed. We found that all doses of the cluster showed similar cell viability, hemolysis, and morphology values, compared to control. Quenching of tryptophan residues of albumin suggests a protein-cluster complex formation. Finally, the cluster showed antiviral activity at 300 µM. These results indicate that the cluster [Mo6Cl14]2− could be intravenously administered in animals at therapeutic doses for further in vivo studies and might be studied as an antiviral agent. Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
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Open AccessArticle Synthesis, Characterization, Antimicrobial and Antiproliferative Activity Evaluation of Cu(II), Co(II), Zn(II), Ni(II) and Pt(II) Complexes with Isoniazid-Derived Compound
Molecules 2017, 22(4), 650; doi:10.3390/molecules22040650
Received: 26 March 2017 / Revised: 11 April 2017 / Accepted: 14 April 2017 / Published: 19 April 2017
Cited by 1 | PDF Full-text (1342 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Hydrazone complexes of Cu(II), Co(II), Zn(II), Ni(II) and Pt(II) with N-isonicotinoyl-N′-(3-metoxy-2 hydroxybenzaldehyde)-hydrazone (HL) were synthesized and characterized by different physico-chemical techniques including elemental and thermal analysis, magnetic susceptibility measurements, molar electric conductivity, as well as IR (infrared), 1
[...] Read more.
Hydrazone complexes of Cu(II), Co(II), Zn(II), Ni(II) and Pt(II) with N-isonicotinoyl-N′-(3-metoxy-2 hydroxybenzaldehyde)-hydrazone (HL) were synthesized and characterized by different physico-chemical techniques including elemental and thermal analysis, magnetic susceptibility measurements, molar electric conductivity, as well as IR (infrared), 1H-NMR and 13C-NMR (hydrogen and carbon nuclear magnetic resonance, UV-Vis (ultraviolet-visible), FAB (fast atom bombardment), EPR (electron paramagnetic resonance), and mass spectroscopies. The crystal structure of ligand was determined by single crystal X-ray diffraction studies. Spectral data showed that hydrazone behaves as an ONO tridentate ligand through the azomethine nitrogen, phenolate and keto oxygen atoms. For the copper(II) complexes, metal–ligand bonding parameters were evaluated from the EPR spectra. These parameters indicate the presence of in-plane π bonding. In addition, the f values of complexes 14 indicate small distortion from planarity. The effect of these complexes on proliferation of human breast cancer (MCF-7 and SKBR-3), human melanoma (A375), lung adenocarcinoma cells (NCI-H1573) and their antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Candida albicans strains were studied and compared with those of free ligand. The ligand and complexes 13 showed significant antimicrobial activity against the Gram-positive bacteria Staphylococcus aureus and Candida albicans in comparison to the control drugs. The complexes 24 could be potential antitumor agents, leading to a significant improvement of the cytotoxic activity when compared with HL. Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
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Open AccessArticle Doxorubicin Conjugated to Glutathione Stabilized Gold Nanoparticles (Au-GSH-Dox) as an Effective Therapeutic Agent for Feline Injection-Site Sarcomas—Chick Embryo Chorioallantoic Membrane Study
Molecules 2017, 22(2), 253; doi:10.3390/molecules22020253
Received: 10 November 2016 / Revised: 31 January 2017 / Accepted: 4 February 2017 / Published: 8 February 2017
Cited by 3 | PDF Full-text (1952 KB) | HTML Full-text | XML Full-text
Abstract
Feline injection-site sarcomas are malignant skin tumours with a high local recurrence rate, ranging from 14% to 28%. The treatment of feline injection-site sarcomas includes radical surgery, radiotherapy and/or chemotherapy. In our previous study it has been demonstrated that doxorubicin conjugated to glutathione-stabilized
[...] Read more.
Feline injection-site sarcomas are malignant skin tumours with a high local recurrence rate, ranging from 14% to 28%. The treatment of feline injection-site sarcomas includes radical surgery, radiotherapy and/or chemotherapy. In our previous study it has been demonstrated that doxorubicin conjugated to glutathione-stabilized gold nanoparticles (Au-GSH-Dox) has higher cytotoxic effects than free doxorubicin for feline fibrosarcoma cell lines with high glycoprotein P activity (FFS1, FFS3). The aim of the present study was to assess the effectiveness of intratumoural injection of Au-GSH-Dox on the growth of tumours from the FFS1 and FFS3 cell lines on chick embryo chorioallantoic membrane. This model has been utilized both in human and veterinary medicine for preclinical oncological studies. The influence of intratumoural injections of Au-GSH-Dox, glutathione-stabilized gold nanoparticles and doxorubicin alone on the Ki-67 proliferation marker was also checked. We demonstrated that the volume ratio of tumours from the FFS1 and FFS3 cell lines was significantly (p < 0.01) decreased after a single intratumoural injection of Au-GSH-Dox, which confirms the positive results of in vitro studies and indicates that Au-GSH-Dox may be a potent new therapeutic agent for feline injection-site sarcomas. Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
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Open AccessArticle In Vitro DNA-Binding, Anti-Oxidant and Anticancer Activity of Indole-2-Carboxylic Acid Dinuclear Copper(II) Complexes
Molecules 2017, 22(1), 171; doi:10.3390/molecules22010171
Received: 4 December 2016 / Revised: 12 January 2017 / Accepted: 16 January 2017 / Published: 20 January 2017
Cited by 2 | PDF Full-text (2838 KB) | HTML Full-text | XML Full-text
Abstract
Indole-2-carboxylic acid copper complex (ICA-Cu) was successfully prepared and characterized through elemental analysis, IR, UV-Vis, 1H-NMR, TG analysis, and molar conductance, and its molecular formula was [Cu2(C9H6O2N)4(H2O)2]·2H2
[...] Read more.
Indole-2-carboxylic acid copper complex (ICA-Cu) was successfully prepared and characterized through elemental analysis, IR, UV-Vis, 1H-NMR, TG analysis, and molar conductance, and its molecular formula was [Cu2(C9H6O2N)4(H2O)2]·2H2O. The binding ability of ICA-Cu to calf thymus DNA (CT-DNA) was examined by fluorescence spectrometry and the viscosity method. The results indicated that, upon the addition of increasing amounts of CT-DNA, the excitation and emission intensity of ICA-Cu decreased obviously and the excitation spectra shifted towards a long wavelength. ICA-Cu could displace ethidium bromide (EB) from the EB-DNA system, making the fluorescence intensity of the EB-DNA system decrease sharply; the quenching constant KSV value was 3.99 × 104 M−1. The emission intensity of the ICA-Cu-DNA system was nearly constant, along with the addition of Na+ in a series of concentrations. The fluorescence of the complex could be protected after the complex interacted with DNA. A viscosity measurement further supported the result that the ICA-Cu complex may interact with DNA in an intercalative binding mode. The antioxidant activities of ICA-Cu were evaluated by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, a hydroxyl radical (OH) scavenging assay, and a 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) assay. The ICA-Cu exhibited the highest inhibitory effects on the ABTS radical (94% inhibition at 60 µM), followed by OH and DPPH radicals (the degrees of inhibition being 71% and 56%, respectively). The in vitro cytotoxicity activity of ICA-Cu against two human breast cancer cell lines, MDA-MB-231 and MCF-7, was investigated by 3-[4,5-dimethyltiazol2-yl]-2.5-diphenyl-tetrazolium bromide (MTT) assay and cellular morphological analysis. The results showed that, upon increasing the concentration of ICA-Cu, an increase was observed in growth-inhibitory activity and the inhibition percentage were greater than 90% at 20 µM in both cell lines. Also, cellular morphological changes in the two cell lines agreed with the cytotoxicity results. Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
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Open AccessArticle Antimicrobial Activity and Urease Inhibition of Schiff Bases Derived from Isoniazid and Fluorinated Benzaldehydes and of Their Copper(II) Complexes
Molecules 2016, 21(12), 1742; doi:10.3390/molecules21121742
Received: 13 November 2016 / Revised: 6 December 2016 / Accepted: 13 December 2016 / Published: 17 December 2016
Cited by 3 | PDF Full-text (2435 KB) | HTML Full-text | XML Full-text
Abstract
In order to evaluate the influence of substitution on biological properties of Schiff bases and their metal complexes, a series of differently substituted fluorine-containing Schiff bases starting from the drug isoniazid (isonicotinylhydrazide) were prepared and their structures were established by single-crystal X-ray diffraction.
[...] Read more.
In order to evaluate the influence of substitution on biological properties of Schiff bases and their metal complexes, a series of differently substituted fluorine-containing Schiff bases starting from the drug isoniazid (isonicotinylhydrazide) were prepared and their structures were established by single-crystal X-ray diffraction. Also, four copper(II) complexes of these Schiff bases were synthesized. The prepared compounds were evaluated for their antimicrobial activity and urease inhibition. Two of the Schiff bases exerted activity against C. albicans. All copper(II) complexes showed excellent inhibitory properties against jack bean urease, considerably better than that of the standard inhibitor acetohydroxamic acid. Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
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Review

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Open AccessReview Metal-Based Nanoparticles for the Treatment of Infectious Diseases
Molecules 2017, 22(8), 1370; doi:10.3390/molecules22081370
Received: 24 July 2017 / Accepted: 15 August 2017 / Published: 18 August 2017
Cited by 1 | PDF Full-text (4598 KB) | HTML Full-text | XML Full-text
Abstract
Infectious diseases can be transmitted and they cause a significant burden on public health globally. They are the greatest world killers and it is estimated that they are responsible for the demise of over 17 million people annually. The impact of these diseases
[...] Read more.
Infectious diseases can be transmitted and they cause a significant burden on public health globally. They are the greatest world killers and it is estimated that they are responsible for the demise of over 17 million people annually. The impact of these diseases is greater in the developing countries. People with compromised immune systems and children are the most affected. Infectious diseases may be caused by bacteria, viruses, and protozoa. The treatment of infectious diseases is hampered by simultaneous resistance to multiple drugs, indicating that there is a serious and pressing need to develop new therapeutics that can overcome drug resistance. This review will focus on the recent reports of metal-based nanoparticles that are potential therapeutics for the treatment of infectious diseases and their biological efficacy (in vitro and in vivo). Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
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Open AccessReview Current Perspective on In Vivo Molecular Imaging of Immune Cells
Molecules 2017, 22(6), 881; doi:10.3390/molecules22060881
Received: 7 April 2017 / Accepted: 19 May 2017 / Published: 26 May 2017
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Abstract
Contemporaneous development of improved immune cell-based therapies, and powerful imaging tools, has prompted growth in technologies for immune cell tracking in vivo. Over the past couple of decades, imaging tools such as magnetic resonance imaging (MRI) and optical imaging have successfully monitored the
[...] Read more.
Contemporaneous development of improved immune cell-based therapies, and powerful imaging tools, has prompted growth in technologies for immune cell tracking in vivo. Over the past couple of decades, imaging tools such as magnetic resonance imaging (MRI) and optical imaging have successfully monitored the trafficking patterns of therapeutic immune cells and assisted the evaluation of the success or failure of immunotherapy. Recent advancements in imaging technology have made imaging an indispensable module of immune cell-based therapies. In this review, emerging applications of non-radiation imaging modalities for the tracking of a range of immune cells are discussed. Applications of MRI, NIR, and other imaging tools have demonstrated the potential of non-invasively surveying the fate of both phagocytic and non-phagocytic immune cells in vivo. Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
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Open AccessReview Metal-Based PSMA Radioligands
Molecules 2017, 22(4), 523; doi:10.3390/molecules22040523
Received: 30 January 2017 / Revised: 13 March 2017 / Accepted: 18 March 2017 / Published: 24 March 2017
Cited by 1 | PDF Full-text (5592 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer is one of the most common malignancies for which great progress has been made in identifying appropriate molecular targets that would enable efficient in vivo targeting for imaging and therapy. The type II integral membrane protein, prostate specific membrane antigen (PSMA)
[...] Read more.
Prostate cancer is one of the most common malignancies for which great progress has been made in identifying appropriate molecular targets that would enable efficient in vivo targeting for imaging and therapy. The type II integral membrane protein, prostate specific membrane antigen (PSMA) is overexpressed on prostate cancer cells in proportion to the stage and grade of the tumor progression, especially in androgen-independent, advanced and metastatic disease, rendering it a promising diagnostic and/or therapeutic target. From the perspective of nuclear medicine, PSMA-based radioligands may significantly impact the management of patients who suffer from prostate cancer. For that purpose, chelating-based PSMA-specific ligands have been labeled with various diagnostic and/or therapeutic radiometals for single-photon-emission tomography (SPECT), positron-emission-tomography (PET), radionuclide targeted therapy as well as intraoperative applications. This review focuses on the development and further applications of metal-based PSMA radioligands. Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
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Other

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Open AccessPerspective Under-Reported Aspects of Platinum Drug Pharmacology
Molecules 2017, 22(3), 382; doi:10.3390/molecules22030382
Received: 24 January 2017 / Accepted: 27 February 2017 / Published: 28 February 2017
Cited by 1 | PDF Full-text (656 KB) | HTML Full-text | XML Full-text
Abstract
Platinum drugs remain the backbone of many antineoplastic regimens. Among the numerous chemical or pharmacological effects of platinum drugs, some aspects tend to be under-reported. Thus, this perspective paper intends to stress some neglected properties of platinum drugs: first, the physico-chemical characteristics (aquation
[...] Read more.
Platinum drugs remain the backbone of many antineoplastic regimens. Among the numerous chemical or pharmacological effects of platinum drugs, some aspects tend to be under-reported. Thus, this perspective paper intends to stress some neglected properties of platinum drugs: first, the physico-chemical characteristics (aquation reaction kinetics) that determine site-specific toxicity; second, the impact on RNA molecules. Knowledge of the ‘RNA world’ has dramatically changed our understanding of cellular and molecular biology. The inherent RNA-crosslinking properties should make platinum-based drugs interact with coding and non-coding RNAs. Third, we will discuss the impact on the immune system, which is now recognized to substantially contribute to chemotherapy efficacy. Together, platinum drugs are in fact old drugs, but are worth re-focusing on. Many aspects are still mysterious but can pave the way to new drugs or an improved application of the already existing compounds. Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
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