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Advances on Chelation in Medicine
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Advances on Chelation in Medicine

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 48481

Special Issue Editor

Prof. Dr. George J. Kontoghiorghes

E-Mail Website
Guest Editor
Postgraduate Research Institute of Science, Technology, Environment and Medicine, CY-3021 Limassol, Cyprus
Interests: chelation therapy; chelation in medicine; chelating drugs; iron chelating drugs in thalassaemia and other diseases of iron overload or imbalance; chelator antioxidants in free radical pathology; chelators and antioxidants in cancer and neurodegenerative diseases; chelating drug design, development and clinical use
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue aims to present the current state of knowledge and new developments in the clinical use, application and effects of chelating drugs. Many areas are covered, including the use of chelating drugs for metal detoxification, as antioxidants, anticancer and anti-infective agents, and as modulators of protein function or pathways associated with disease. In addition, we will cover the use of chelator–metal complexes for increasing essential metal absorption; in clinical diagnosis, e.g., Tc and Gd complexes; as anticancer agents, e.g., Pt, Cu and Ga complexes. Important areas also include recent advances on the molecular, pharmacological, toxicological and other properties of chelating drugs, as well as new mechanisms of action, posology and interactions with other drugs. Such information is pivotal for designing therapeutic strategies for the effective treatment of millions of patients with many diseases such as thalassaemia, cancer and neurodegenerative diseases. It is envisaged that chelation in multifactorial diseases can play a major role and be used as a main, alternative or adjuvant therapy. In this context, improved therapeutic strategies could be developed and adopted based on combination therapies, target-specific and prodrug design methods and other aspects that can fulfil personalised medicine characteristics.

Prof. George J. Kontoghiorghes
Guest Editor

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.

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Keywords

  • chelation therapy
  • metal detoxification
  • chelator antioxidants
  • chelator–metal complex applications
  • chelating drug effects
  • deferiprone
  • deferoxamine
  • deferasirox
  • mimosine
  • maltol iron treatments
  • EDTA
  • DTPA
  • penicillamine
  • triethylenetetramine
  • dexrazoxane
  • iron overload treatment
  • thalassaemia treatment
  • iron deficiency treatment
  • iron metabolic disorders treatment
  • copper overload treatment
  • heavy metal detoxification
  • cancer treatment
  • neurodegenerative disease treatment
  • tissue damage treatment
  • kidney disease treatment
  • ischaemia/reperfusion injury treatment
  • antimicrobial treatments
  • mitochondrial disease treatment
  • ageing treatment

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

8 pages, 381 KiB  
Editorial
Advances on Chelation and Chelator Metal Complexes in Medicine
by George J. Kontoghiorghes
Int. J. Mol. Sci. 2020, 21(7), 2499; https://doi.org/10.3390/ijms21072499 - 3 Apr 2020
Cited by 41 | Viewed by 6449
Abstract
Metal ions such as iron, copper and zinc are essential for life [...] Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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Research

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32 pages, 9807 KiB  
Article
Discovery of Novel 3-Hydroxyquinazoline-2,4(1H,3H)-Dione Derivatives: A Series of Metal Ion Chelators with Potent Anti-HCV Activities
by Yang Cao, Abudumijiti Aimaiti, Zeyun Zhu, Lu Zhou and Deyong Ye
Int. J. Mol. Sci. 2022, 23(11), 5930; https://doi.org/10.3390/ijms23115930 - 25 May 2022
Cited by 1 | Viewed by 2105
Abstract
Millions of people worldwide suffer from acute or chronic liver inflammation caused by the hepatitis C virus (HCV). Metal ion chelators have achieved widespread success in the development of antiviral drugs. Some inhibitors with metal ion chelating structures have been proven to have [...] Read more.
Millions of people worldwide suffer from acute or chronic liver inflammation caused by the hepatitis C virus (HCV). Metal ion chelators have achieved widespread success in the development of antiviral drugs. Some inhibitors with metal ion chelating structures have been proven to have good inhibitory activities on non-structural protein 5B (NS5B) polymerase. However, most of the reported metal ion chelators showed poor anti-HCV potency at the cellular level. Hence, we designed and synthesized a series of 3-hydroxyquinazoline-2,4(1H,3H)-dione derivatives with novel metal ion chelating structures. Typical compounds such as 21h, 21k, and 21t showed better anti-HCV activities than ribavirin with EC50 values less than 10 μM. 21t is currently known as one of the metal ion chelators with the best anti-HCV potency (EC50 = 2.0 μM) at the cellular level and has a better therapeutic index (TI > 25) as compared to ribavirin and the reported compound 6. In the thermal shift assay, the representative compounds 21e and 21k increased the melting temperature (Tm) of NS5B protein solution by 1.6 °C and 2.1 °C, respectively, at the test concentration, indicating that these compounds may exert an anti-HCV effect by targeting NS5B. This speculation was also supported by our molecular docking studies and ultraviolet-visible (UV-Vis) spectrophotometry assay, in which the possibility of binding of 3-hydroxyquinazoline-2,4(1H,3H)-diones with Mg2+ in the NS5B catalytic center was observed. Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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16 pages, 4371 KiB  
Article
Redox Interactions of Vitamin C and Iron: Inhibition of the Pro-Oxidant Activity by Deferiprone
by Viktor A. Timoshnikov, Tatyana V. Kobzeva, Nikolay E. Polyakov and George J. Kontoghiorghes
Int. J. Mol. Sci. 2020, 21(11), 3967; https://doi.org/10.3390/ijms21113967 - 31 May 2020
Cited by 98 | Viewed by 12518
Abstract
Ascorbic acid (AscH2) is one of the most important vitamins found in the human diet, with many biological functions including antioxidant, chelating, and coenzyme activities. Ascorbic acid is also widely used in medical practice especially for increasing iron absorption and as [...] Read more.
Ascorbic acid (AscH2) is one of the most important vitamins found in the human diet, with many biological functions including antioxidant, chelating, and coenzyme activities. Ascorbic acid is also widely used in medical practice especially for increasing iron absorption and as an adjuvant therapeutic in iron chelation therapy, but its mode of action and implications in iron metabolism and toxicity are not yet clear. In this study, we used UV–Vis spectrophotometry, NMR spectroscopy, and EPR spin trapping spectroscopy to investigate the antioxidant/pro-oxidant effects of ascorbic acid in reactions involving iron and the iron chelator deferiprone (L1). The experiments were carried out in a weak acidic (pH from 3 to 5) and neutral (pH 7.4) medium. Ascorbic acid exhibits predominantly pro-oxidant activity by reducing Fe3+ to Fe2+, followed by the formation of dehydroascorbic acid. As a result, ascorbic acid accelerates the redox cycle Fe3+ ↔ Fe2+ in the Fenton reaction, which leads to a significant increase in the yield of toxic hydroxyl radicals. The analysis of the experimental data suggests that despite a much lower stability constant of the iron–ascorbate complex compared to the FeL13 complex, ascorbic acid at high concentrations is able to substitute L1 in the FeL13 chelate complex resulting in the formation of mixed L12AscFe complex. This mixed chelate complex is redox stable at neutral pH = 7.4, but decomposes at pH = 4–5 during several minutes at sub-millimolar concentrations of ascorbic acid. The proposed mechanisms play a significant role in understanding the mechanism of action, pharmacological, therapeutic, and toxic effects of the interaction of ascorbic acid, iron, and L1. Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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19 pages, 2588 KiB  
Article
Manipulating the In Vivo Behaviour of 68Ga with Tris(Hydroxypyridinone) Chelators: Pretargeting and Blood Clearance
by Cinzia Imberti, Pierre Adumeau, Julia E. Blower, Fahad Al Salemee, Julia Baguña Torres, Jason S. Lewis, Brian M. Zeglis, Samantha Y. A. Terry and Philip J. Blower
Int. J. Mol. Sci. 2020, 21(4), 1496; https://doi.org/10.3390/ijms21041496 - 22 Feb 2020
Cited by 11 | Viewed by 3332
Abstract
Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based [...] Read more.
Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based on gallium-68 and the chelator THPMe as a high-affinity pair capable of combining in vivo. After confirming the ability of THPMe to bind 68Ga in vivo at low concentrations, the bifunctional THPMe-NCS was conjugated to a humanised huA33 antibody targeting the A33 glycoprotein. Imaging experiments performed in nude mice bearing A33-positive SW1222 colorectal cancer xenografts compared pretargeting (100 μg of THPMe-NCS-huA33, followed after 24 h by 8–10 MBq of 68Ga3+) with both a directly labelled radioimmunoconjugate (89Zr-DFO-NCS-huA33, 88 μg, 7 MBq) and a 68Ga-only negative control (8–10 MBq of 68Ga3+). Imaging was performed 25 h after antibody administration (1 h after 68Ga3+ administration for negative control). No difference between pretargeting and the negative control was observed, suggesting that pretargeting via metal chelation is not feasible using this model. However, significant accumulation of “unchelated” 68Ga3+ in the tumour was found (12.9 %ID/g) even without prior administration of THPMe-NCS-huA33, though tumour-to-background contrast was impaired by residual activity in the blood. Therefore, the 68Ga-only experiment was repeated using THPMe (20 μg, 1 h after 68Ga3+ administration) to clear circulating 68Ga3+, producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THPMe as a 68Ga clearing agent in imaging applications with gallium citrate. Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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14 pages, 3281 KiB  
Article
Associative Interactions among Zinc, Apolipoprotein E, and Amyloid-β in the Amyloid Pathology
by Shin Bi Oh, Jung Ah Kim, SuJi Park and Joo-Yong Lee
Int. J. Mol. Sci. 2020, 21(3), 802; https://doi.org/10.3390/ijms21030802 - 25 Jan 2020
Cited by 15 | Viewed by 4015
Abstract
Zinc and apolipoprotein E (apoE) are reportedly involved in the pathology of Alzheimer’s disease. To investigate the associative interaction among zinc, apoE, and amyloid-β (Aβ) and its role in amyloid pathogenesis, we performed various biochemical and immunoreactive analyses using brain tissues of Tg2576 [...] Read more.
Zinc and apolipoprotein E (apoE) are reportedly involved in the pathology of Alzheimer’s disease. To investigate the associative interaction among zinc, apoE, and amyloid-β (Aβ) and its role in amyloid pathogenesis, we performed various biochemical and immunoreactive analyses using brain tissues of Tg2576 mice and synthetic Aβ and apoE peptides. On amyloid plaques or in brain lysates of Tg2576 mice, apoE and Aβ immunoreactivities increased after zinc chelation and were restored by its subsequent replacement. Zinc depletion dissociated apoE/Aβ complexes or larger-molecular sizes of Aβ oligomers/aggregates into smaller-molecular sizes of apoE and/or Aβ monomers/complexes. In the presence of zinc, synthetic apoE and/or Aβ peptides aggregated into larger-molecular sizes of oligomers or complexes. Endogenous proteases or plasmin in brain lysates degraded apoE and/or Aβ complexes, and their proteolytic activity increased with zinc depletion. These biochemical findings suggest that zinc associates with apoE and Aβ to encourage the formation of apoE/Aβ complexes or large aggregates, raising the deposition of zinc-rich amyloid plaques. In turn, the presence of abundant zinc around and within apoE/Aβ complexes may block the access or activity of Aβ-degrading antibodies or proteases. These results support the plausibility of chelation strategy aiming at reducing amyloid pathology in Alzheimer’s disease. Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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16 pages, 2540 KiB  
Article
Deferoxamine Enhanced Mitochondrial Iron Accumulation and Promoted Cell Migration in Triple-Negative MDA-MB-231 Breast Cancer Cells Via a ROS-Dependent Mechanism
by Chunli Chen, Shicheng Wang and Ping Liu
Int. J. Mol. Sci. 2019, 20(19), 4952; https://doi.org/10.3390/ijms20194952 - 8 Oct 2019
Cited by 34 | Viewed by 7382
Abstract
In our previous study, Deferoxamine (DFO) increased the iron concentration by upregulating the expression levels of TfR1 and DMT1 and exacerbated the migration of triple-negative breast cancer cells. However, the mechanisms of iron distribution and utilization in triple-negative breast cancer cells with a [...] Read more.
In our previous study, Deferoxamine (DFO) increased the iron concentration by upregulating the expression levels of TfR1 and DMT1 and exacerbated the migration of triple-negative breast cancer cells. However, the mechanisms of iron distribution and utilization in triple-negative breast cancer cells with a DFO-induced iron deficiency are still unclear. In this study, triple-negative MDA-MB-231 and estrogen receptor (ER)-positive MCF-7 breast cancer cells were used to investigate the mechanisms of iron distribution and utilization with a DFO-induced iron deficiency. We found that the mitochondrial iron concentration was elevated in MDA-MB-231 cells, while it was decreased in MCF-7 cells after DFO treatment. The cellular and mitochondrial reactive oxygen species (ROS) levels increased in both breast cancer cell types under DFO-induced iron-deficient conditions. However, the increased ROS levels had different effects on the different breast cancer cell types: Cell viability was inhibited and apoptosis was enhanced in MCF-7 cells, but cell viability was maintained and cell migration was promoted in MDA-MB-231 cells through the ROS/NF-κB and ROS/TGF-β signaling pathways. Collectively, this study suggests that under DFO-induced iron-deficient conditions, the increased mitochondrial iron levels in triple-negative MDA-MB-231 breast cancer cells would generate large amounts of ROS to activate the NF-κB and TGF-β signaling pathways to promote cell migration. Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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Review

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20 pages, 762 KiB  
Review
Current Biomedical Use of Copper Chelation Therapy
by Silvia Baldari, Giuliana Di Rocco and Gabriele Toietta
Int. J. Mol. Sci. 2020, 21(3), 1069; https://doi.org/10.3390/ijms21031069 - 6 Feb 2020
Cited by 119 | Viewed by 11754
Abstract
Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the [...] Read more.
Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials. Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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