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Special Issue "Metal-Based Drugs"

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

Deadline for manuscript submissions: closed (31 December 2019).

Special Issue Editors

Prof. Dr. Carlo Santini
Website
Guest Editor
School of Science and Technology, Chemistry Division, University of Camerino, via Sant’Agostino 1, 62032 Camerino (MC), Italy
Interests: metal-based drugs; coordination chemistry; functional metal complexes; hybrid materials; inorganic and organometallic chemistry; scorpionate ligands; phosphanes; N-heterocyclic carbenes
Special Issues and Collections in MDPI journals
Prof. Dr. Maura Pellei
Website
Guest Editor
School of Science and Technology, Chemistry Division, University of Camerino, via Sant’Agostino 1, 62032 Camerino (MC), Italy
Interests: metal-based drugs; bioinorganic chemistry; coordination chemistry; inorganic materials; organometalllic chemistry; copper; scorpionate ligands; phosphanes N-heterocyclic carbenes
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Metals have been considered for millennia to have medicinal values, and with the advent of modern medicine, numerous metal-based drugs have proven to be highly effective in clinical settings. Many different metal ions have shown activity against a range of diseases, beyond their well-known applications in cancer (cisplatin) or rheumatoid arthritis (auranofin). The widespread medicinal applications of metal-based compounds have captured the attention of the scientific community in recent years for the variety of compounds studied owing to their wide spectrum of reactivity and the width of their applications in medicinal chemistry for the synthesis of chemotherapeutic and diagnostic molecules not readily accessible to organic compounds.

This Special Issue will cover a selection of recent research and review articles to collect and disseminate some of the most significant and recent contributions in the field of metals used in medicine, highlighting their pharmacological applications in several diseases, such as cancers, diabetes, osteoporosis, and as diagnostic agents.

Prof. Dr. Carlo Santini
Prof. Dr. Maura Pellei
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 semimonthly 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 2000 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

  • metals in medicine
  • coordination complexes
  • organometallics
  • anticancer agents
  • antibacterial agents
  • metal-based diagnostic agents
  • radiopharmaceuticals
  • chelation therapy
  • chemotherapy

Published Papers (8 papers)

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Research

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Open AccessArticle
Cytotoxic Activity of Organotin(IV) Derivatives with Triazolopyrimidine Containing Exocyclic Oxygen Atoms
Molecules 2020, 25(4), 859; https://doi.org/10.3390/molecules25040859 - 15 Feb 2020
Cited by 1
Abstract
In this study cytotoxicity of organotin(IV) compounds with 1,2,4-triazolo[1,5-a]pyrimidines, Me3Sn(5tpO) (1), n-Bu3Sn(5tpO) (2), Me3Sn(mtpO) (3), n-Bu3Sn(mtpO) (4), n-Bu3Sn(HtpO2) (5), [...] Read more.
In this study cytotoxicity of organotin(IV) compounds with 1,2,4-triazolo[1,5-a]pyrimidines, Me3Sn(5tpO) (1), n-Bu3Sn(5tpO) (2), Me3Sn(mtpO) (3), n-Bu3Sn(mtpO) (4), n-Bu3Sn(HtpO2) (5), Ph3Sn(HtpO2) (6) where 5HtpO = 4,5-dihydro-5-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, HmtpO = 4,7-dihydro-5-methyl-7-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, and H2tpO2 = 4,5,6,7-tetrahydro-5,7- dioxo-[1,2,4]triazolo-[1,5-a]-pyrimidine, was assessed on three different human tumor cell lines: HCT-116 (colorectal carcinoma), HepG2 (hepatocarcinoma) and MCF-7 (breast cancer). While 1 and 3 were inactive, compounds 2, 4, 5 and 6 inhibited the growth of the three tumor cell lines with IC50 values in the submicromolar range and showed high selectivity indexes towards the tumor cells (SI > 90). The mechanism of cell death triggered by the organotin(IV) derivatives, investigated on HCT-116 cells, was apoptotic, as evident from the externalization of phosphatidylserine to the cell surface, and occurred via the intrinsic pathway with fall of mitochondrial inner membrane potential and production of reactive oxygen species. While compound 6 arrested the cell progression in the G2/M cell cycle phase and increased p53 and p21 levels, compounds 2, 4 and 5 blocked cell duplication in the G1 phase without affecting the expression of either of the two tumor suppressor proteins. Compounds 1 and 2 were also investigated using single crystal X-ray diffraction and found to be, in both cases, coordination polymers forming 1 D chains based on metal-ligand interactions. Interestingly, for n-Bu3Sn(5tpO)(2) H-bonding interactions between 5tpO ligands belonging to adjacent chains were also detected that resemble the “base-pairing” assembly and could be responsible for the higher biological activity compared to compound 1. In addition, they are the first example of bidentate N(3), O coordination for the 5HtpO ligand on two adjacent metal atoms. Full article
(This article belongs to the Special Issue Metal-Based Drugs)
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Open AccessArticle
Discovery of Cisplatin Binding to Thymine and Cytosine on a Single-Stranded Oligodeoxynucleotide by High Resolution FT-ICR Mass Spectrometry
Molecules 2019, 24(10), 1852; https://doi.org/10.3390/molecules24101852 - 14 May 2019
Cited by 3
Abstract
The clinically widely-used anticancer drug, cisplatin, binds strongly to DNA as a DNA-damaging agent. Herein, we investigated the interaction of cisplatin with a 15-mer single-stranded C,T-rich oligodeoxynucleotide, 5′-CCTT4CTT7G8C9T10TCTCC-3′ (ODN15), using ultra-high resolution Fourier [...] Read more.
The clinically widely-used anticancer drug, cisplatin, binds strongly to DNA as a DNA-damaging agent. Herein, we investigated the interaction of cisplatin with a 15-mer single-stranded C,T-rich oligodeoxynucleotide, 5′-CCTT4CTT7G8C9T10TCTCC-3′ (ODN15), using ultra-high resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) in conjunction with tandem mass spectrometry (top-down MS). Top-down MS analysis with collision-induced dissociation (CID) fragmentation of the mono-platinated and di-platinated ODN15 provided abundant and informative Pt-containing or Pt-free a/[a − B], w and internal fragments, allowing the unambiguous identification of T4, T7, C9, and T10 as the platination sites on the cisplatin-ODN15 adducts. These results revealed that, in addition to the well-established guanine site, the unexpected thermodynamic binding of cisplatin to cytosine and thymine bases was also evident at the oligonucleotide level. Furthermore, the binding models of cisplatin with cytosine and thymine bases were built as the Pt coordinated to cytosine-N(3) and thymine-N(3) with displacement of the proton or tautomerization of thymine. These findings contribute to a better understanding of the mechanism of action of cisplatin and its preference for gene loci when the drug binds to cellular DNA, and also demonstrate the great potential and superiority of FT-ICR MS in studying the interactions of metallodrugs with large biomolecules. Full article
(This article belongs to the Special Issue Metal-Based Drugs)
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Open AccessFeature PaperArticle
Syntheses and Biological Studies of Cu(II) Complexes Bearing Bis(pyrazol-1-yl)- and Bis(triazol-1-yl)-acetato Heteroscorpionate Ligands
Molecules 2019, 24(9), 1761; https://doi.org/10.3390/molecules24091761 - 07 May 2019
Cited by 3
Abstract
Copper(II) complexes of bis(pyrazol-1-yl)- and bis(triazol-1-yl)-acetate heteroscorpionate ligands have been synthesized. The copper(II) complexes [HC(COOH)(pzMe2)2]Cu[HC(COO)(pzMe2)2]·ClO4, [HC(COOH)(pz)2]2Cu(ClO4)2 (pzMe2 = 3,5-dimethylpyrazole; pz = pyrazole) were prepared by [...] Read more.
Copper(II) complexes of bis(pyrazol-1-yl)- and bis(triazol-1-yl)-acetate heteroscorpionate ligands have been synthesized. The copper(II) complexes [HC(COOH)(pzMe2)2]Cu[HC(COO)(pzMe2)2]·ClO4, [HC(COOH)(pz)2]2Cu(ClO4)2 (pzMe2 = 3,5-dimethylpyrazole; pz = pyrazole) were prepared by the reaction of Cu(ClO4)2·6H2O with bis(3,5-dimethylpyrazol-1-yl)acetic acid (HC(COOH)(pzMe2)2) and bis(pyrazol-1-yl)acetic acid (HC(COOH)(pz)2) ligands in ethanol solution. The copper(II) complex [HC(COOH)(tz)2]2Cu(ClO4)2·CH3OH (tz = 1,2,4-triazole) was prepared by the reaction of Cu(ClO4)2·6H2O with bis(1,2,4-triazol-1-yl)acetic acid (HC(COOH)(tz)2) ligand in methanol solution. The synthesized Cu(II) complexes, as well as the corresponding uncoordinated ligands, were evaluated for their cytotoxic activity in monolayer and 3D spheroid cancer cell cultures with different Pt(II)-sensitivity. The results showed that [HC(COOH)(pzMe2)2]Cu[HC(COO)(pzMe2)2]·ClO4 was active against cancer cell lines derived from solid tumors at low IC50 and this effect was retained in the spheroid model. Structure and ultra-structure changes of treated cancer cells analyzed by Transmission Electron Microscopy (TEM) highlighted the induction of a cytoplasmic vacuolization, thus suggesting paraptotic-like cancer cell death triggering. Full article
(This article belongs to the Special Issue Metal-Based Drugs)
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Open AccessFeature PaperArticle
Effect of Manganese Chloride and of Cotreatment with Cadmium Chloride on the In Vitro Proliferative, Motile, and Invasive Behavior of MDA-MB231 Breast Cancer Cells
Molecules 2019, 24(7), 1205; https://doi.org/10.3390/molecules24071205 - 27 Mar 2019
Cited by 2
Abstract
We examined the dose–response effect of MnCl2 on the proliferative behavior of triple-negative breast cancer MDA-M231 cells vs. immortalized HB2 cells from breast epithelium taken as nontumoral counterparts. We also tested the effect of MnCl2 on tumor cell invasiveness in vitro [...] Read more.
We examined the dose–response effect of MnCl2 on the proliferative behavior of triple-negative breast cancer MDA-M231 cells vs. immortalized HB2 cells from breast epithelium taken as nontumoral counterparts. We also tested the effect of MnCl2 on tumor cell invasiveness in vitro by evaluating the relative invasion indexes through Boyden chamber assays. Moreover, we checked whether cotreatment with both MnCl2 and CdCl2 could modify the observed biological response by MDA-MB231 cells. Our results show a promotional impact of MnCl2 on cell proliferation, with 5 µM concentration inducing the more pronounced increase after 96-h exposure, which is not shared by HB2 cells. Exposure to 5 µM MnCl2 induced also an elevation of the relative invasion index of cancer cells. The Mn-mediated stimulatory effects were counteracted by cotreatment with CdCl2. These data support the concept that human exposure to high environmental concentrations of Mn may increase the risk of carcinogenesis and metastasis by prompting the expansion and dissemination of triple-negative breast cancer cells. On the other hand, the Mn-counteracting anticancer property of Cd looks promising and deserves a more detailed characterization of the involved intracellular targets aimed to the molecular modeling of specific antineoplastic agents against malignant breast cancer spreading. Full article
(This article belongs to the Special Issue Metal-Based Drugs)
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Review

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Open AccessReview
Ferrocene-Based Compounds with Antimalaria/Anticancer Activity
Molecules 2019, 24(19), 3604; https://doi.org/10.3390/molecules24193604 - 07 Oct 2019
Cited by 11
Abstract
Malaria and cancer are chronic diseases. The challenge with drugs available for the treatment of these diseases is drug toxicity and resistance. Ferrocene is a potent organometallic which have been hybridized with other compounds resulting in compounds with enhanced biological activity such as [...] Read more.
Malaria and cancer are chronic diseases. The challenge with drugs available for the treatment of these diseases is drug toxicity and resistance. Ferrocene is a potent organometallic which have been hybridized with other compounds resulting in compounds with enhanced biological activity such as antimalarial and anticancer. Drugs such as ferroquine were developed from ferrocene and chloroquine. It was tested in the 1990s as an antimalarial and is still an effective antimalarial. Many researchers have reported ferrocene compounds as potent compounds useful as anticancer and antimalarial agents when hybridized with other pharmaceutical scaffolds. This review will be focused on compounds with ferrocene moieties that exhibit either an anticancer or antimalarial activity. Full article
(This article belongs to the Special Issue Metal-Based Drugs)
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Open AccessReview
Iridium(III) Complexes Targeting Apoptotic Cell Death in Cancer Cells
Molecules 2019, 24(15), 2739; https://doi.org/10.3390/molecules24152739 - 28 Jul 2019
Cited by 10
Abstract
Targeting apoptosis is a principal strategy in the design of anticancer drugs. In recent years, non-platinum-based scaffolds have been exploited as viable candidates for the exploitation of anticancer agents with potentially lower toxicity than the widely used cisplatin analogues. This review highlights the [...] Read more.
Targeting apoptosis is a principal strategy in the design of anticancer drugs. In recent years, non-platinum-based scaffolds have been exploited as viable candidates for the exploitation of anticancer agents with potentially lower toxicity than the widely used cisplatin analogues. This review highlights the latest advances in developing iridium(III) complexes as anticancer agents that act particularly via targeting apoptotic cell death in cancer cells. Full article
(This article belongs to the Special Issue Metal-Based Drugs)
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Open AccessFeature PaperReview
NMR-Based Metabolomics in Metal-Based Drug Research
Molecules 2019, 24(12), 2240; https://doi.org/10.3390/molecules24122240 - 15 Jun 2019
Cited by 3
Abstract
Thanks to recent advances in analytical technologies and statistical capabilities, the application field of metabolomics has increased significantly. Currently, this approach is used to investigate biological substrates looking for metabolic profile alterations, diseases markers, and drug effects. In particular, NMR spectroscopy has shown [...] Read more.
Thanks to recent advances in analytical technologies and statistical capabilities, the application field of metabolomics has increased significantly. Currently, this approach is used to investigate biological substrates looking for metabolic profile alterations, diseases markers, and drug effects. In particular, NMR spectroscopy has shown great potential as a detection technique, mainly for the ability to detect multiple (10s to 100s) metabolites at once without separation. Only in recent years has the NMR-based metabolomic approach been extended to investigate the cell metabolic alterations induced by metal-based antitumor drug administration. As expected, these studies are mainly focused on platinum complexes, but some palladium and ruthenium compounds are also under investigation. The use of a metabolomics approach was very effective in assessing tumor response to drugs and providing insights into the mechanism of action and resistance. Therefore, metabolomics may open new perspectives into the development of metal-based drugs. In particular, it has been shown that NMR-based, in vitro metabolomics is a powerful tool for detecting variations of the cell metabolites induced by the metal drug exposure, thus offering also the possibility of identifying specific markers for in vivo monitoring of tumor responsiveness to anticancer treatments. Full article
(This article belongs to the Special Issue Metal-Based Drugs)
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Other

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Open AccessLetter
Interdisciplinary Tasks in the Cyclotron Production of Radiometals for Medical Applications. The Case of 47Sc as Example
Molecules 2019, 24(3), 444; https://doi.org/10.3390/molecules24030444 - 26 Jan 2019
Cited by 1
Abstract
The growing number of cyclotrons of different sizes installed in the territory has given a strong impulse to the production of conventional and emerging radionuclides for medical applications. In particular, the great advantage of using medical cyclotrons is the possibility to produce on-site, [...] Read more.
The growing number of cyclotrons of different sizes installed in the territory has given a strong impulse to the production of conventional and emerging radionuclides for medical applications. In particular, the great advantage of using medical cyclotrons is the possibility to produce on-site, when needed (on-demand), with medical radionuclides of interest encouraging the personalized medicine approach. Radiometals satisfy the ideal characteristics that radionuclides should have for routine employment in nuclear medicine, especially since they have a robust chemistry suitable to synthetize stable in vivo radiopharmaceuticals with high radiochemical yields. In this letter several interdisciplinary aspects involved in the radiometals cyclotron production cycle are summarized focusing the attention on cyclotron production facilities, target material, and chemical processing available for medical applications. As an example, the current status and recent development in the production of the theranostic radionuclide scandium-47 have been reported. Full article
(This article belongs to the Special Issue Metal-Based Drugs)
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