Special Issue "Applications of Medicinal Bioinorganic Chemistry"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 29 April 2022.

Special Issue Editors

Prof. Dr. Guido Crisponi
E-Mail Website
Guest Editor
Faculty of Biology and Pharmacy, University of Cagliari, Cagliari, Italy
Interests: analytical chemistry; bioinorganic chemistry; chelation therapy
Dr. Alicia Dominguez-Martin
E-Mail Website
Guest Editor
Department of Inorganic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Interests: bioinorganic chemistry; nucleic acids; molecular recognition; multicomponent pharmaceutical materials; co-drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In this Special Issue of Pharmaceuticals entitled “Applications of Medicinal Bioinorganic Chemistry”, we aim to explore the potential of bioinorganic chemistry applied to medicinal chemistry. The growing field of bioinorganic chemistry has expanded the knowledge of the functions of metal ions in the human organism, their homeostatic control, and the influence of disequilibrium on the onset and progression of different pathologies.

The therapeutic use of metal-based drugs dates back to the starting of civilization. A number of metal-based drugs can be found in the pharmacopoeia at the start of the last century, such as mercuric ions in the treatment of syphilis; silver as one of the few drugs capable of healing infections, burns, and wounds, and preventing contagious diseases; gold in the treatment of rheumatoid arthritis;  or  lithium as an antidepressant.

Nowadays, the use of metal ions in the diagnosis and treatment of diseases is continuously increasing, finding applications as contrast agents for CT and MRI, in developing essential diagnosis techniques in modern medicine, and as drugs for clinical use in anticancer therapy. The knowledge of the molecular base of neurodegenerative diseases (Parkinson’s, Alzheimer’s, etc.) has opened the way to new drugs for the treatment of these burdensome diseases. In medicinal chemistry, chelating agents have been used for the scavenging of toxic metal ions, in particular iron chelators for thalassemia patients, which extended both life expectance and quality of life.

In this Special Issue, Pharmaceuticals welcomes original research articles and reviews devoted to life science, pharmaceutical science, and clinical science research within the field of applications of medicinal bioinorganic chemistry.

Prof. Dr. Guido Crisponi
Dr. Alicia Dominguez-Martin
Guest Editors

Manuscript Submission Information

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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. Pharmaceuticals 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 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

  • Metal-based drugs
  • Contrast agents
  • Anticancer drugs
  • Neurodegenerative diseases
  • Chelating agents
  • Ionophores

Published Papers (11 papers)

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Research

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Article
Chemical Characterization and Biological Evaluation of New Cobalt(II) Complexes with Bioactive Ligands, 2-Picolinehydroxamic Acid and Reduced Schiff Base N-(2-Hydroxybenzyl)alanine, in Terms of DNA Binding and Antimicrobial Activity
Pharmaceuticals 2021, 14(12), 1254; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14121254 - 02 Dec 2021
Viewed by 574
Abstract
Five new heteroligand cobalt(II) complexes with 2-picolinehydroxamic acid and reduced Schiff base, N-(2-hydroxybenzyl)alanine, were formed in an aqueous solution over a wide pH range. The coordination properties of ligands towards the metal ion were determined using a pH-metric method, and then the [...] Read more.
Five new heteroligand cobalt(II) complexes with 2-picolinehydroxamic acid and reduced Schiff base, N-(2-hydroxybenzyl)alanine, were formed in an aqueous solution over a wide pH range. The coordination properties of ligands towards the metal ion were determined using a pH-metric method, and then the speciation model was confirmed by UV–Vis studies. A stacking interaction between the Schiff base phenol ring and the 2-picolinehydroxamic acid pyridine ring was found to improve the stability of the heteroligand species, indicating more effective coordination in mixed-ligand complexes than in their respective binary systems. The antimicrobial properties of heteroligand complexes were determined against Gram-negative and Gram-positive bacteria, as well as fungal strains. The formulation demonstrated the highest bacteriostatic and bactericidal activity (3.65 mM) against two strains of Gram-negative Helicobacter pylori bacteria and towards Candida albicans and Candida glabrata; this is important due to the potential co-existence of these microorganisms in the gastric milieu and their role in the development of gastritis. The binary complexes in the cobalt(II)—2-picolinehydroxamic acid system and 2-picolinehydroxamic acid were not cytotoxic against L929 mouse fibroblasts, neither freshly prepared solutions or after two weeks’ storage. By comparison, the heteroligand complexes within the range 0.91–3.65 mM diminished the metabolic activity of L929 cells, which was correlated with increased damage to cell nuclei. The concentration of the heteroligand species increased over time; therefore, the complexes stored for two weeks exhibited stronger anticellular toxicity than the freshly prepared samples. The complexes formed in an aqueous solution under physiological pH effectively bound to calf thymus DNA in an intercalative manner. This DNA-binding ability may underpin the antimicrobial/antifungal activity of the heteroligand complexes and their ability to downregulate the growth of eukaryotic cells. Full article
(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)
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Article
Thermodynamic Study of Oxidovanadium(IV) with Kojic Acid Derivatives: A Multi-Technique Approach
Pharmaceuticals 2021, 14(10), 1037; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14101037 - 12 Oct 2021
Viewed by 552
Abstract
The good chelating properties of hydroxypyrone (HPO) derivatives towards oxidovanadium(IV) cation, VIVO2+, constitute the precondition for the development of new insulin-mimetic and anticancer compounds. In the present work, we examined the VIVO2+ complex formation equilibria of [...] Read more.
The good chelating properties of hydroxypyrone (HPO) derivatives towards oxidovanadium(IV) cation, VIVO2+, constitute the precondition for the development of new insulin-mimetic and anticancer compounds. In the present work, we examined the VIVO2+ complex formation equilibria of two kojic acid (KA) derivatives, L4 and L9, structurally constituted by two kojic acid units linked in position 6 through methylene diamine and diethyl-ethylenediamine, respectively. These chemical systems have been characterized in solution by the combined use of various complementary techniques, as UV-vis spectrophotometry, potentiometry, NMR and EPR spectroscopy, ESI-MS spectrometry, and DFT calculations. The thermodynamic approach allowed proposing a chemical coordination model and the calculation of the complex formation constants. Both ligands L4 and L9 form 1:1 binuclear complexes at acidic and physiological pHs, with various protonation degrees in which two KA units coordinate each VIVO2+ ion. The joined use of different techniques allowed reaching a coherent vision of the complexation models of the two ligands toward oxidovanadium(IV) ion in aqueous solution. The high stability of the formed species and the binuclear structure may favor their biological action, and represent a good starting point toward the design of new pharmacologically active vanadium species. Full article
(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)
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Article
Dicopper(II)-EDTA Chelate as a Bicephalic Receptor Model for a Synthetic Adenine Nucleoside
Pharmaceuticals 2021, 14(5), 426; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050426 - 02 May 2021
Cited by 1 | Viewed by 979
Abstract
In the extensive field of metal ions, their interactions with nucleic acids, and their constituents, the main aim of this work is to develop a metal chelate suitable to recognize two molecules of an adenine nucleoside. For this purpose, the dinuclear chelate Cu [...] Read more.
In the extensive field of metal ions, their interactions with nucleic acids, and their constituents, the main aim of this work is to develop a metal chelate suitable to recognize two molecules of an adenine nucleoside. For this purpose, the dinuclear chelate Cu2 (µ-EDTA) (ethylenediaminetetraacetate(4-) ion (EDTA)) is chosen as a bicephalic receptor model for N9-(2-hydroxyethyl)adenine (9heade). A one-pot synthesis is reported to obtain the compound [Cu22-EDTA)(9heade)2(H2O)4]·3H2O, which has been characterized by single-crystal X-ray diffraction and various spectral, thermal, and magnetic methods. The complex unit is a centro-symmetric molecule, where each Cu (II) center is chelated by a half-EDTA, and is further surrounded by an N7-dentate 9heade nucleoside and two non-equivalent trans-O-aqua molecules. The metal chelate-nucleoside molecular recognition is referred to as an efficient cooperation between the Cu-N7(9heade) coordination bond and a (9heade)N6-H···O(carboxyl, EDTA) interligand interaction. Theoretical calculations are also made to account for the relevance of this interaction. The extreme weakness with which each water molecule binds to the metal center disturbs the thermal stability and the infrared (FT-IR) and electron spin resonance (ESR) spectra of the compound. Full article
(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)
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Article
Synthesis, Characterization and Antiproliferative Evaluation of Pt(II) and Pd(II) Complexes with a Thiazine-Pyridine Derivative Ligand
Pharmaceuticals 2021, 14(5), 395; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050395 - 22 Apr 2021
Viewed by 1023
Abstract
Chemical, pharmacological, and clinical research on anticancer coordination complexes has led to noteworthy anticancer drugs such as cisplatin, carboplatin and oxaliplatin. Although these compounds are effective chemotherapeutic agents in the treatment of different tumors, they are associated with high toxicity and numerous side [...] Read more.
Chemical, pharmacological, and clinical research on anticancer coordination complexes has led to noteworthy anticancer drugs such as cisplatin, carboplatin and oxaliplatin. Although these compounds are effective chemotherapeutic agents in the treatment of different tumors, they are associated with high toxicity and numerous side effects. Several studies have shown that the range of platinum complexes with antitumor activity is not limited to structural analogs of cisplatin. Therefore, the development of convenient anticancer drugs that can be effectively used for the treatment of human tumors has become the main goal of most research groups in this field. In this sense, active platinum complexes without NH groups, transplatinum complexes, multinuclear complexes, cationic complexes, and several classes of palladium(II) complexes have emerged. Herein, the synthesis and characterization of two Pt(II) or Pd(II) complexes with PyTz (2-(2-pyridyl)iminotetrahydro-1,3-thiazine), a thiazine derivative ligand, with the formula [MCl2(PyTz)]·C2H6O (M = Pt(II) or Pd(II)) were reported. The potential anticancer ability of both complexes was evaluated in epithelial cervix carcinoma HeLa, human ovary adenocarcinoma SK-OV-3, human histiocytic lymphoma U-937, and human promyelocytic leukemia HL-60 cell lines. Interestingly, the Pt(II) complex showed great cytotoxic potential against all tumor cell lines tested, whereas the Pd(II) complex displayed slight antitumor actions. Full article
(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)
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Article
Deciphering the H-Bonding Preference on Nucleoside Molecular Recognition through Model Copper(II) Compounds
Pharmaceuticals 2021, 14(3), 244; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030244 - 09 Mar 2021
Cited by 3 | Viewed by 600
Abstract
The synthetic nucleoside acyclovir is considered an outstanding model of the natural nucleoside guanosine. With the purpose of deepening on the influence and nature of non-covalent interactions regarding molecular recognition patterns, three novel Cu(II) complexes, involving acyclovir (acv) and the ligand receptor N-(2-hydroxyethyl)ethylenediamine [...] Read more.
The synthetic nucleoside acyclovir is considered an outstanding model of the natural nucleoside guanosine. With the purpose of deepening on the influence and nature of non-covalent interactions regarding molecular recognition patterns, three novel Cu(II) complexes, involving acyclovir (acv) and the ligand receptor N-(2-hydroxyethyl)ethylenediamine (hen), have been synthesized and thoroughly characterized. The three novel compounds introduce none, one or two acyclovir molecules, respectively. Molecular recognition has been evaluated using single crystal X-ray diffraction. Furthermore, theoretical calculations and other physical methods such as thermogravimetric analysis, infrared and UV-Vis spectroscopy, electron paramagnetic resonance and magnetic measurements have been used. Theoretical calculations are in line with experimental results, supporting the relevance of the [metal-N7(acv) + H-bond] molecular recognition pattern. It was also shown that (hen)O-H group is used as preferred H-donor when it is found within the basal coordination plane, since the higher polarity of the terminal (hen)O-H versus the N-H group favours its implication. Otherwise, when (hen)O-H occupies the distal coordination site, (hen)N-H groups can take over. Full article
(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)
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Article
Hyaluronic Acid-Modified and Doxorubicin-Loaded Gold Nanoparticles and Evaluation of Their Bioactivity
Pharmaceuticals 2021, 14(2), 101; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020101 - 28 Jan 2021
Cited by 3 | Viewed by 769
Abstract
Functionalized gold nanoparticles (AuNPs) have been successfully used in many fields as a result of having low cytotoxicity, good biocompatibility, excellent optical properties, and their ability to target cancer cells. Here, we synthesized AuNP carriers that were modified by hyaluronic acid (HA), polyethylene [...] Read more.
Functionalized gold nanoparticles (AuNPs) have been successfully used in many fields as a result of having low cytotoxicity, good biocompatibility, excellent optical properties, and their ability to target cancer cells. Here, we synthesized AuNP carriers that were modified by hyaluronic acid (HA), polyethylene glycol (PEG), and adipic dihydrazide (ADH). The antitumor drug doxorubicin (Dox) was loaded into AuNP carriers and attached chemically. The Au nanocomposite [email protected] was able to disperse uniformly in aqueous solution, with a diameter of 15 nm. The results of a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that AuNP carriers displayed very little toxicity toward cells in high doses, although the antitumor properties of Au nanocomposites were significantly enhanced. Cellular uptake experiments demonstrated that AuNPs modified with hyaluronic acid were more readily ingested by HepG2 and HCT-116 cells, as they have a large number of CD44 receptors. A series of experiments measuring apoptosis such as Rh123 and annexin V-FITC staining, and analysis of mitochondrial membrane potential (MMP) analysis, indicated that apoptosis played a role in the inhibition of cell proliferation by [email protected] Excessive production of reactive oxygen species (ROS) was the principal mechanism by which the Au nanocomposites inhibited cell proliferation, leading to apoptosis. Thus, the Au nanocomposites, which allowed cell imaging in real-time and induced apoptosis in specific cell types, represent theragnostic agents with potential for future clinical applications in bowel cancer. Full article
(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)
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Article
Combined Effect of Caspase-Dependent and Caspase-Independent Apoptosis in the Anticancer Activity of Gold Complexes with Phosphine and Benzimidazole Derivatives
Pharmaceuticals 2021, 14(1), 10; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010010 - 24 Dec 2020
Cited by 3 | Viewed by 1508
Abstract
Since the potential anticancer activity of auranofin was discovered, gold compounds have attracted interest with a view to developing anticancer agents that follow cytotoxic mechanisms other than cisplatin. Two benzimidazole gold(I) derivatives containing triphenylphosphine (Au(pben)(PPh3)) (1) or triethylphosphine (Au(pben)(PEt [...] Read more.
Since the potential anticancer activity of auranofin was discovered, gold compounds have attracted interest with a view to developing anticancer agents that follow cytotoxic mechanisms other than cisplatin. Two benzimidazole gold(I) derivatives containing triphenylphosphine (Au(pben)(PPh3)) (1) or triethylphosphine (Au(pben)(PEt3)) (2) were prepared and characterized by standard techniques. X-ray crystal structures for 1 and 2 were solved. The cytotoxicity of 1 and 2 was tested in human neuroblastoma SH-SY5Y cells. Cells were incubated with compounds for 24 h with concentrations ranging from 10 µM to 1 nM, and the half-maximal inhibitory concentration (IC50) was determined. 1 and 2 showed an IC50 of 2.7 and 1.6 µM, respectively. In order to better understand the type of cell death induced by compounds, neuroblastoma cells were stained with Annexin-FITC and propidium iodide. The fluorescence analysis revealed that compounds were inducing apoptosis; however, pre-treatment with the caspase inhibitor Z-VAD did not reduce cell death. Analysis of compound effects on caspase-3 activity and reactive oxygen species (ROS) production in SH-SY5Y cells revealed an antiproliferative ability mediated through oxidative stress and both caspase-dependent and caspase-independent mechanisms. Full article
(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)
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Review

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Review
Monofunctional Platinum(II) Anticancer Agents
Pharmaceuticals 2021, 14(2), 133; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020133 - 07 Feb 2021
Cited by 7 | Viewed by 1134
Abstract
Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side effects. Much effort has been made to circumvent the drug resistance and general toxicity of these [...] Read more.
Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side effects. Much effort has been made to circumvent the drug resistance and general toxicity of these drugs. Among multifarious designs, monofunctional platinum(II) complexes with a general formula of [Pt(3A)Cl]+ (A: Ammonia or amine) stand out as a class of “non-traditional” anticancer agents hopeful to overcome the defects of current platinum drugs. This review aims to summarize the development of monofunctional platinum(II) complexes in recent years. They are classified into four categories: fluorescent complexes, photoactive complexes, targeted complexes, and miscellaneous complexes. The intention behind the designs is either to visualize the cellular distribution, or to reduce the side effects, or to improve the tumor selectivity, or inhibit the cancer cells through non-DNA targets. The information provided by this review may inspire researchers to conceive more innovative complexes with potent efficacy to shake off the drawbacks of platinum anticancer drugs. Full article
(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)
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Review
Mercury Toxicity and Detection Using Chromo-Fluorogenic Chemosensors
Pharmaceuticals 2021, 14(2), 123; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020123 - 05 Feb 2021
Cited by 7 | Viewed by 959
Abstract
Mercury (Hg), this non-essential heavy metal released from both industrial and natural sources entered into living bodies, and cause grievous detrimental effects to the human health and ecosystem. The monitoring of Hg2+ excessive accumulation can be beneficial to fight against the risk [...] Read more.
Mercury (Hg), this non-essential heavy metal released from both industrial and natural sources entered into living bodies, and cause grievous detrimental effects to the human health and ecosystem. The monitoring of Hg2+ excessive accumulation can be beneficial to fight against the risk associated with mercury toxicity to living systems. Therefore, there is an emergent need of novel and facile analytical approaches for the monitoring of mercury levels in various environmental, industrial, and biological samples. The chromo-fluorogenic chemosensors possess the attractive analytical parameters of low-cost, enhanced detection ability with high sensitivity, simplicity, rapid on-site monitoring ability, etc. This review was narrated to summarize the mercuric ion selective chromo-fluorogenic chemosensors reported in the year 2020. The design of sensors, mechanisms, fluorophores used, analytical performance, etc. are summarized and discussed. Full article
(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)
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Review
Zinc(II)—The Overlooked Éminence Grise of Chloroquine’s Fight against COVID-19?
Pharmaceuticals 2020, 13(9), 228; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13090228 - 01 Sep 2020
Cited by 9 | Viewed by 4500
Abstract
Zn(II) is an inhibitor of SARS-CoV-2′s RNA-dependent RNA polymerase, and chloroquine and hydroxychloroquine are Zn(II) ionophores–this statement gives a curious mind a lot to think about. We show results of the first clinical trials on chloroquine (CQ) and hydroxychloroquine (HCQ) in the [...] Read more.
Zn(II) is an inhibitor of SARS-CoV-2′s RNA-dependent RNA polymerase, and chloroquine and hydroxychloroquine are Zn(II) ionophores–this statement gives a curious mind a lot to think about. We show results of the first clinical trials on chloroquine (CQ) and hydroxychloroquine (HCQ) in the treatment of COVID-19, as well as earlier reports on the anticoronaviral properties of these two compounds and of Zn(II) itself. Other FDA-approved Zn(II) ionophores are given a decent amount of attention and are thought of as possible COVID-19 therapeutics. Full article
(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)
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Review
Gold Nanoparticles: A New Golden Era in Oncology?
Pharmaceuticals 2020, 13(8), 192; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13080192 - 12 Aug 2020
Cited by 7 | Viewed by 1437
Abstract
In recent years, the spectrum of possible applications of gold in diagnostics and therapeutic approaches in clinical practice has changed significantly, becoming surprisingly broad. Nowadays, gold-based therapeutic agents are used in the therapy of multiple human diseases, ranging from degenerative to infectious diseases [...] Read more.
In recent years, the spectrum of possible applications of gold in diagnostics and therapeutic approaches in clinical practice has changed significantly, becoming surprisingly broad. Nowadays, gold-based therapeutic agents are used in the therapy of multiple human diseases, ranging from degenerative to infectious diseases and, in particular, to cancer. At the basis of these performances of gold, there is the development of new gold-based nanoparticles, characterized by a promising risk/benefit ratio that favors their introduction in clinical trials. Gold nanoparticles appear as attractive elements in nanomedicine, a branch of modern clinical medicine, which combines high selectivity in targeting tumor cells and low toxicity. Thanks to these peculiar characteristics, gold nanoparticles appear as the starting point for the development of new gold-based therapeutic strategies in oncology. Here, the new gold-based therapeutic agents developed in recent years are described, with particular emphasis on the possible applications in clinical practice as anticancer agents, with the aim that their application will give rise to a new golden age in oncology and a breakthrough in the fight against cancer. Full article
(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)
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