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Advances on Chelation and Chelator Metal Complexes in Medicine

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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 November 2021) | Viewed by 14165

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Special Issue Editor

Prof. Dr. George J. Kontoghiorghes

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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
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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. Dr. 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.

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

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

Published Papers (4 papers)

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Editorial

Jump to: Review

8 pages, 251 KiB

Open AccessEditorial

Questioning Established Theories and Treatment Methods Related to Iron and Other Metal Metabolic Changes, Affecting All Major Diseases and Billions of Patients

by George J. Kontoghiorghes

Int. J. Mol. Sci. 2022, 23(3), 1364; https://doi.org/10.3390/ijms23031364 - 25 Jan 2022

Cited by 1 | Viewed by 1935

Abstract

The medical and scientific literature is dominated by highly cited historical theories and findings [...] Full article

(This article belongs to the Special Issue Advances on Chelation and Chelator Metal Complexes in Medicine)

Review

Jump to: Editorial

32 pages, 2057 KiB

Open AccessReview

New Iron Metabolic Pathways and Chelation Targeting Strategies Affecting the Treatment of All Types and Stages of Cancer

by George J. Kontoghiorghes

Int. J. Mol. Sci. 2022, 23(22), 13990; https://doi.org/10.3390/ijms232213990 - 13 Nov 2022

Cited by 12 | Viewed by 3105

Abstract

There is new and increasing evidence from in vitro, in vivo and clinical studies implicating the pivotal role of iron and associated metabolic pathways in the initiation, progression and development of cancer and in cancer metastasis. New metabolic and toxicity mechanisms and pathways, as well as genomic, transcription and other factors, have been linked to cancer and many are related to iron. Accordingly, a number of new targets for iron chelators have been identified and characterized in new anticancer strategies, in addition to the classical restriction of/reduction in iron supply, the inhibition of transferrin iron delivery, the inhibition of ribonucleotide reductase in DNA synthesis and high antioxidant potential. The new targets include the removal of excess iron from iron-laden macrophages, which affects anticancer activity; the modulation of ferroptosis; ferritin iron removal and the control of hyperferritinemia; the inhibition of hypoxia related to the role of hypoxia-inducible factor (HIF); modulation of the function of new molecular species such as STEAP4 metalloreductase and the metastasis suppressor N-MYC downstream-regulated gene-1 (NDRG1); modulation of the metabolic pathways of oxidative stress damage affecting mitochondrial function, etc. Many of these new, but also previously known associated iron metabolic pathways appear to affect all stages of cancer, as well as metastasis and drug resistance. Iron-chelating drugs and especially deferiprone (L1), has been shown in many recent studies to fulfill the role of multi-target anticancer drug linked to the above and also other iron targets, and has been proposed for phase II trials in cancer patients. In contrast, lipophilic chelators and their iron complexes are proposed for the induction of ferroptosis in some refractory or recurring tumors in drug resistance and metastasis where effective treatments are absent. There is a need to readdress cancer therapy and include therapeutic strategies targeting multifactorial processes, including the application of multi-targeting drugs involving iron chelators and iron–chelator complexes. New therapeutic protocols including drug combinations with L1 and other chelating drugs could increase anticancer activity, decrease drug resistance and metastasis, improve treatments, reduce toxicity and increase overall survival in cancer patients. Full article

(This article belongs to the Special Issue Advances on Chelation and Chelator Metal Complexes in Medicine)

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29 pages, 4611 KiB

Open AccessReview

Mechanistic Insights of Chelator Complexes with Essential Transition Metals: Antioxidant/Pro-Oxidant Activity and Applications in Medicine

by Viktor A. Timoshnikov, Olga Yu. Selyutina, Nikolay E. Polyakov, Victoria Didichenko and George J. Kontoghiorghes

Int. J. Mol. Sci. 2022, 23(3), 1247; https://doi.org/10.3390/ijms23031247 - 23 Jan 2022

Cited by 24 | Viewed by 3477

Abstract

The antioxidant/pro-oxidant activity of drugs and dietary molecules and their role in the maintenance of redox homeostasis, as well as the implications in health and different diseases, have not yet been fully evaluated. In particular, the redox activity and other interactions of drugs with essential redox metal ions, such as iron and copper, need further investigation. These metal ions are ubiquitous in human nutrition but also widely found in dietary supplements and appear to exert major effects on redox homeostasis in health, but also on many diseases of free radical pathology. In this context, the redox mechanistic insights of mainly three prototype groups of drugs, namely alpha-ketohydroxypyridines (alpha-hydroxypyridones), e.g., deferiprone, anthraquinones, e.g., doxorubicin and thiosemicarbazones, e.g., triapine and their metal complexes were examined; details of the mechanisms of their redox activity were reviewed, with emphasis on the biological implications and potential clinical applications, including anticancer activity. Furthermore, the redox properties of these three classes of chelators were compared to those of the iron chelating drugs and also to vitamin C, with an emphasis on their potential clinical interactions and future clinical application prospects in cancer, neurodegenerative and other diseases. Full article

(This article belongs to the Special Issue Advances on Chelation and Chelator Metal Complexes in Medicine)

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34 pages, 3102 KiB

Open AccessReview

New Era in the Treatment of Iron Deficiency Anaemia Using Trimaltol Iron and Other Lipophilic Iron Chelator Complexes: Historical Perspectives of Discovery and Future Applications

by George J. Kontoghiorghes, Annita Kolnagou, Theodora Demetriou, Marina Neocleous and Christina N. Kontoghiorghe

Int. J. Mol. Sci. 2021, 22(11), 5546; https://doi.org/10.3390/ijms22115546 - 24 May 2021

Cited by 21 | Viewed by 4967

Abstract

The trimaltol iron complex (International Non-proprietary Name: ferric maltol) was originally designed, synthesised, and screened in vitro and in vivo in 1980–1981 by Kontoghiorghes G.J. following his discovery of the novel alpha-ketohydroxyheteroaromatic (KHP) class of iron chelators (1978–1981), which were intended for clinical use, including the treatment of iron deficiency anaemia (IDA). Iron deficiency anaemia is a global health problem affecting about one-third of the world’s population. Many (and different) ferrous and ferric iron complex formulations are widely available and sold worldwide over the counter for the treatment of IDA. Almost all such complexes suffer from instability in the acidic environment of the stomach and competition from other dietary molecules or drugs. Natural and synthetic lipophilic KHP chelators, including maltol, have been shown in in vitro and in vivo studies to form stable iron complexes, to transfer iron across cell membranes, and to increase iron absorption in animals. Trimaltol iron, sold as Feraccru or Accrufer, was recently approved for clinical use in IDA patients in many countries, including the USA and in EU countries, and was shown to be effective and safe, with a better therapeutic index in comparison to other iron formulations. Similar properties of increased iron absorption were also shown by lipophilic iron complexes of 8-hydroxyquinoline, tropolone, 2-hydroxy-4-methoxypyridine-1-oxide, and related analogues. The interactions of the KHP iron complexes with natural chelators, drugs, metal ions, proteins, and other molecules appear to affect the pharmacological and metabolic effects of both iron and the KHP chelators. A new era in the treatment of IDA and other possible clinical applications, such as theranostic and anticancer formulations and metal radiotracers in diagnostic medicine, are envisaged from the introduction of maltol, KHP, and similar lipophilic chelators. Full article

(This article belongs to the Special Issue Advances on Chelation and Chelator Metal Complexes in Medicine)

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