Taming glutathione potentiates metallodrug action

Nguyen, Hieu D.; H., Loi

doi:10.1016/j.cbpa.2022.102213

Cited by 13 publications

(9 citation statements)

References 53 publications

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“…Indeed, while promising in vitro , complex 19 exhibited low sensitivity to exogenously added sodium formate in preliminary live-cell confocal microscopy experiments (Figure SI-18), consistent with an in vitro assay showing strong inhibition of sulfonamide amine-type complex 19 to cellular thiols such as cysteine and glutathione (GSH) (Table SI-5). Overcoming the inhibitory activity of cellular thiols on transition metal catalysts is a challenging issue, , and while Ward and co-workers have designed protein-encapsulated iridium complexes that can sterically guard a sulfonamide amine iridium complex from inhibitory thiol chelation, demonstration of this strategy in live cells remains elusive . On the other hand, Do and colleagues have shown the capacity of half-sandwich pyridine amide complexes such as complex 9 to operate in live cells, ,, and in vitro assays showed that while aldehyde reduction in the presence of cellular thiols (GSH or cysteine) is slowed, TH reactivity with sodium formate, complex 9 , and fluorophore F-1 is still operative (Table SI-5).…”

Section: Resultsmentioning

confidence: 99%

A Transfer Hydrogenation Approach to Activity-Based Sensing of Formate in Living Cells

Crossley,

Tenney,

Pham

et al. 2024

J. Am. Chem. Soc.

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Formate is a major reactive carbon species in one-carbon metabolism, where it serves as an endogenous precursor for amino acid and nucleic acid biosynthesis and a cellular source of NAD(P)H. On the other hand, aberrant elevations in cellular formate are connected to progression of serious diseases, including cancer and Alzheimer's disease. Traditional methods for formate detection in biological environments often rely on sample destruction or extensive processing, resulting in a loss of spatiotemporal information. To help address these limitations, here we present the design, synthesis, and biological evaluation of a first-generation activity-based sensing system for live-cell formate imaging that relies on iridium-mediated transfer hydrogenation chemistry. Formate facilitates an aldehyde-to-alcohol conversion on various fluorophore scaffolds to enable fluorescence detection of this one-carbon unit, including through a two-color ratiometric response with internal calibration. The resulting two-component probe system can detect changes in formate levels in living cells with a high selectivity over potentially competing biological analytes. Moreover, this activity-based sensing system can visualize changes in endogenous formate fluxes through alterations of one-carbon pathways in cell-based models of human colon cancer, presaging the potential utility of this chemical approach to probe the continuum between one-carbon metabolism and signaling in cancer and other diseases.

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Section: Resultsmentioning

confidence: 99%

A Transfer Hydrogenation Approach to Activity-Based Sensing of Formate in Living Cells

Crossley,

Tenney,

Pham

et al. 2024

J. Am. Chem. Soc.

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“…Further catalyst design should aim at increasing the compounds’ stability with respect to inactivation by intracellular nucleophiles and at introducing targeting moieties (e.g., bioconjugation to targeting peptides). Alternatively, a few strategies have been proposed to tame GSH in living systems which could be implemented at early stages of metallodrug design …”

Section: Anticancer Organometallic Drugsmentioning

confidence: 99%

Metals in Cancer Research: Beyond Platinum Metallodrugs

Casini,

Pöthig

2024

ACS Cent. Sci.

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The discovery of the medicinal properties of platinum complexes has fueled the design and synthesis of new anticancer metallodrugs endowed with unique modes of action (MoA). Among the various families of experimental antiproliferative agents, organometallics have emerged as ideal platforms to control the compounds' reactivity and stability in a physiological environment. This is advantageous to efficiently deliver novel prodrug activation strategies, as well as to design metallodrugs acting only via noncovalent interactions with their pharmacological targets. Noteworthy, another justification for the advance of organometallic compounds for therapy stems from their ability to catalyze bioorthogonal reactions in cancer cells.When not yet ideal as drug leads, such compounds can be used as selective chemical tools that benefit from the advantages of catalytic amplification to either label the target of interest (e.g., proteins) or boost the output of biochemical signals. Examples of metallodrugs for the so-called "catalysis in cells" are considered in this Outlook together with other organometallic drug candidates. The selected case studies are discussed in the frame of more general challenges in the field of medicinal inorganic chemistry.

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“…There are a few anticancer compounds whose GSH-depleting competency in destroying cancer cells has been reported, although their efficacy may be interrupted by some other factors. Therefore, the interference of GSH with metallodrugs can be restricted by following several strategies, such as depleting the concentration of GSH in cells and exploiting GSH as an activator as well as shielding metallodrugs from GSH binding . The main objective of this Review is to highlight the importance of GSH depletion in cancer therapy.…”

Section: Metallotherapeutics Toward Glutathione Depletion and Cancer ...mentioning

confidence: 99%

Glutathione Depletion and Stalwart Anticancer Activity of Metallotherapeutics Inducing Programmed Cell Death: Opening a New Window for Cancer Therapy

Roy,

Paira

2024

ACS Omega

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The cellular defense system against exogenous substances makes therapeutics inefficient as intracellular glutathione (GSH) exhibits an astounding antioxidant activity in scavenging reactive oxygen species (ROS) or reactive nitrogen species (RNS) or other free radicals produced by the therapeutics. In the cancer cell microenvironment, the intracellular GSH level becomes exceptionally high to fight against oxidative stress created by the production of ROS/RNS or any free radicals, which are the byproducts of intracellular redox reactions or cellular respiration processes. Thus, in order to maintain redox homeostasis for survival of cancer cells and their rapid proliferation, the GSH level starts to escalate. In this circumstance, the administration of anticancer therapeutics is in vain, as the elevated GSH level reduces their potential by reduction or by scavenging the ROS/RNS they produce. Therefore, in order to augment the therapeutic potential of anticancer agents against elevated GSH condition, the GSH level must be depleted by hook or by crook. Hence, this Review aims to compile precisely the role of GSH in cancer cells, the importance of its depletion for cancer therapy and examples of anticancer activity of a few selected metal complexes which are able to trigger cancer cell death by depleting the GSH level.

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Taming glutathione potentiates metallodrug action

Cited by 13 publications

References 53 publications

A Transfer Hydrogenation Approach to Activity-Based Sensing of Formate in Living Cells

A Transfer Hydrogenation Approach to Activity-Based Sensing of Formate in Living Cells

Metals in Cancer Research: Beyond Platinum Metallodrugs

Glutathione Depletion and Stalwart Anticancer Activity of Metallotherapeutics Inducing Programmed Cell Death: Opening a New Window for Cancer Therapy

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