Transition metal chelators, pro-chelators, and ionophores as small molecule cancer chemotherapeutic agents

Steinbrueck, Axel; Sedgwick, Adam; Brewster, James T.; Yan, Kai-Cheng; Shang, Yan; Knoll, Daniel M.; Vargas‐Zúñiga, Gabriela I.; He, Xiao‐Peng; Tian, He; Sessler, Jonathan L.

doi:10.1039/c9cs00373h

Cited by 150 publications

(122 citation statements)

References 46 publications

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“…In contrast, Cu 2+ (moderately soft cation) prefers thiols, thiones and sp 2 hybridized nitrogens, such as imines, hydrazones and heterocycles, with the formation of tetra‐, penta‐, and hexacoordinate complexes with square planar, trigonal bipyramidal and octahedral geometries [48] . In both cases, considering an idealized scenario where the formed stable metal complex should not significantly dissociate under physiological environment conditions, the kinetics of ligand formation should be also evaluated when designing a metal chelation therapeutic strategy [49] …”

Section: Coppermentioning

confidence: 99%

“…In this regard, so‐called pro‐chelators are emerging as potential candidates for an effective cancer therapy. A pro‐chelator is an extension of the term pro‐drug and is defined as a compound obtained from the chemical modification of a chelator, aimed at increasing membrane permeability and improving their selectivity for cancer cells while suppressing the propensity for metal chelation in an undesired compartment within the body [49] . These compounds exploit the altered features of the tumor micro‐environment (e. g. pH and/or redox state) to activate chelation.…”

Section: Coppermentioning

confidence: 99%

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Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics

et al. 2021

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Copper is an essential transition metal frequently increased in cancer known to strongly influence essential cellular processes. Targeted therapy protocols utilizing both novel and repurposed drug agents initially demonstrate strong efficacy, before failing in advanced cancers as drug resistance develops and relapse occurs. Overcoming this limitation involves the development of strategies and protocols aimed at a wider targeting of the underlying molecular changes. Receptor Tyrosine Kinase signaling pathways, epigenetic mechanisms and cell metabolism are among the most common therapeutic targets, with molecular investigations increasingly demonstrating the strong influence each mechanism exerts on the others. Interestingly, all these mechanisms can be influenced by intracellular copper. We propose that copper chelating agents, already in clinical trial for multiple cancers, may simultaneously target these mechanisms across a wide variety of cancers, serving as an excellent candidate for targeted combination therapy. This review summarizes the known links between these mechanisms, copper, and copper chelation therapy.

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Section: Coppermentioning

confidence: 99%

Section: Coppermentioning

confidence: 99%

Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics

et al. 2021

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“…Metal cation release can then be activated by either a low local concentration of the metal cation or the presence of a stimulus that favors metal cation release. Due to the reversibility of the metal binding process, the ionophore may repeatedly transport metal cations across membranes [25].…”

Section: Discussionmentioning

confidence: 99%

“…Another aspect of potential ionophore molecules is the geometry of the most stable form of the ionophore-metal cation complex [25]. Ionophores are flexible, the final spatial orientation of the complexes includes configurational or conformational remodeling of the ionophore to accommodate the internalization of the metal ion.…”

Section: Discussionmentioning

confidence: 99%

“…Ionophores are flexible, the final spatial orientation of the complexes includes configurational or conformational remodeling of the ionophore to accommodate the internalization of the metal ion. Ionophores, in general, are molecules having backbones of a range of different topologies that include oxygen or nitrogen atoms that are strategically spaced [25]. The liganding atoms include a variety of functional groups, including ether, alcohol, carboxyl and amide, among others.…”

Section: Discussionmentioning

confidence: 99%

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Theoretical Three-Dimensional Zinc Complexes with Glutathione, Amino Acids and Flavonoids

et al. 2021

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Zinc plays an important role in the regulation of many cellular functions; it is a signaling molecule involved in the transduction of several cascades in response to intra and extracellular stimuli. Labile zinc is a small fraction of total intracellular zinc, that is loosely bound to proteins and is easily interchangeable. At the cellular level, several molecules can bind labile zinc and promote its passage across lipophilic membranes. Such molecules are known as ionophores. Several of these compounds are known in the scientific literature, but most of them can be harmful to human health and are therefore not allowed for medical use. We here performed a theoretical three-dimensional study of known zinc ionophores, together with a computational energetic study and propose that some dietary flavonoids, glutathione and amino acids could form zinc complexes and facilitate the transport of zinc, with the possible biological implications and potential health benefits of these natural compounds. The study is based on obtaining a molecular conformational structure of the zinc complexes with the lowest possible energy content. The discovery of novel substances that act as zinc ionophores is an attractive research topic that offers exciting opportunities in medicinal chemistry. We propose that these novel complexes could be promising candidates for drug design to provide new solutions for conditions and diseases related to zinc deficiency or impairment derived from the dysregulation of this important metal.

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A Hollow Amorphous Bimetal Organic Framework for Synergistic Cuproptosis/Ferroptosis/Apoptosis Anticancer Therapy via Disrupting Intracellular Redox Homeostasis and Copper/Iron Metabolisms

Qian

Hou

et al. 2022

Adv Funct Materials

134

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Cuproptosis is a very newly recognized regulated cell death modality that is distinct from known death mechanisms and shows enormous prospect in cancer treatment. However, its efficacy is copper-dependent and restricted by strictly regulated copper metabolism. Herein, a novel copper/iron hybrid hollow amorphous metal organic framework (HaMOF) is developed as an oxidative stress amplifier and copper/iron metabolic disrupter for synergistic cuproptosis/ferroptosis/apoptosis anticancer therapy. The HaMOF is fabricated from Cu 2+ , 3,3′-dithiobis(propionohydrazide) and Fe 3+ via an unsaturated coordination-etching integration strategy, and then doxorubicin is loaded followed by surface decoration with hyaluronan. The obtained DOX@ Fe/CuTH exhibits tumor microenvironment-triggered catalytic therapeutic property, wherein it can amplify cellular oxidative stress by simultaneously boosting H 2 O 2 production and depleting glutathione. Moreover, it can cause mitochondrial dysfunction and downregulate the expressions of copper transporter ATP7A and iron transporter FPN 1, thereby leading to metabolic disorders and high retentions of copper/iron in cytoplasm for •OH generation. The overloaded Cu 2+ can cause lipoylated protein dihydrolipoamide S-acetyltransferase aggregation and lead to cellular cuproptosis. Collectively, both augmented oxidative stress and overloaded copper/iron induce potent ferroptosis, which synergizes with cuproptosis and DOX-mediated apoptosis to efficiently suppress tumor growth. This bimetallic hollow nanoplatform provides a new therapeutic modality paradigm to boost cuproptosis-related therapies.

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Transition metal chelators, pro-chelators, and ionophores as small molecule cancer chemotherapeutic agents

Abstract: Transition metal chelators and ionophores have shown promise as alternative chemotherapeutic strategies by selectively altering the concentrations of iron, copper, and zinc in cancer cells.

Cited by 150 publications

References 46 publications

Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics

Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics

Theoretical Three-Dimensional Zinc Complexes with Glutathione, Amino Acids and Flavonoids

A Hollow Amorphous Bimetal Organic Framework for Synergistic Cuproptosis/Ferroptosis/Apoptosis Anticancer Therapy via Disrupting Intracellular Redox Homeostasis and Copper/Iron Metabolisms

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