Prochelators triggered by hydrogen peroxide provide hexadentate iron coordination to impede oxidative stress

Leed, Marina G.D.; Wolkow, Natalie; Pham, David M.; Daniel, Catherine; Dunaief, Joshua L.; Franz, Katherine J.

doi:10.1016/j.jinorgbio.2011.05.023

Cited by 29 publications

(18 citation statements)

References 49 publications

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“…The two fluorescent prochelators contain either a pinacol boronic ester, FloB, or a self-immolative pinacol boronic ester, FloB-SI. As we have shown previously, masking a metal chelator directly with a boronic ester renders the prochelator ineffective at binding metal ions until activation with H 2 O 2 [17, 19, 21]. Several other groups have employed a self-immolative boronic ester as a protecting group or mask for H 2 O 2 responsive small molecules, dendritic chains, and metalloproteinase inhibitors [20, 22–24].…”

Section: Resultsmentioning

confidence: 99%

A cell-permeable fluorescent prochelator responds to hydrogen peroxide and metal ions by decreasing fluorescence

Hyman¹,

Franz²

2012

Inorganica Chimica Acta

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Described here is the development of two boronic ester-based fluorescent prochelators, FloB (2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-4(5)-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene-hydrazinocarbonyl]-benzoic acid) and FloB-SI (2-(6-hydroxy-3-oxo-3Hxanthen-9-yl)-4(5)-[2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)-benzylidene-hydrazinocarbonyl]-benzoic acid) that show a fluorescence response to a variety of transition metal ions only after reaction with H2O2. Both prochelators’ boronic ester masks are oxidized by H2O2 to reveal a fluorescein-tagged metal chelator, FloS (4(5)-(2-hydroxy-benzylidenehydrazinocarbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-benzoic acid). Chelation of Fe3+ or Cu2+ elicits a 70% decrease in the emission signal of FloS, while Zn2+, Ni2+, and Co2+ produce a more modest fluorescence decrease. The conversion of FloB to FloS proceeds in organic solvents, but hydrolytic decomposition of its hydrazone backbone is observed in aqueous solution. However, FloB-SI oxidizes cleanly with H2O2 within 1 h in aqueous solutions to produce FloS. Fluorescence microscopy studies in HeLa cells with FloB-SI show that the sensor’s fluorescence intensity remains unchanged until incubation with exogenous H2O2, which results in a decreased fluorescent signal. Incubation with a competitive chelator restores the emission response, thus suggesting that FloB-SI can effectively report on a H2O2-induced increase in intracellular labilized metal.

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Section: Resultsmentioning

confidence: 99%

A cell-permeable fluorescent prochelator responds to hydrogen peroxide and metal ions by decreasing fluorescence

Hyman¹,

Franz²

2012

Inorganica Chimica Acta

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“…To expand this concept, prochelators of hexadentate ligands have been investigated. 55 The most successful prochelator investigated was 39.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…It is noteworthy that the potential therapeutic window of the chelating agent significantly increases masking the metal binding site with H 2 O 2 responsive elements as 39 shows very little toxicity whereas its chelator causes complete cell death at higher concentrations. 55 The strategy of masking iron cheletors with a moiety/group has also been applied for deferasirox, a clinically used drug in iron overload diseases. A prochelator that contains a self-immolative boronic ester masking group has been synthesized (40).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Prochelator strategies for site-selective activation of metal chelators

Oliveri

Vecchio

2016

Journal of Inorganic Biochemistry

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“…Figure 3 showcases a series of boronate-masked prochelators we developed based on the “removal” strategy for conditionally passivating Fe and Cu against Fenton reactivity. 12–16 …”

Section: Introductionmentioning

confidence: 99%

Stimulus-Responsive Prochelators for Manipulating Cellular Metals

Wang

Franz

2016

Acc. Chem. Res.

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CONSPECTUS Metal ions are essential for a wide range of physiological processes, but they can also be toxic if not appropriately regulated by a complex network of metal trafficking proteins. Intervention in cellular metal distribution with small molecule or peptide chelating agents has promising therapeutic potential to harness metals to fight disease. Molecular outcomes associated with forming metal-chelate interactions in situ include altering concentration and subcellular metal distribution, inhibiting metalloenzymes, enhancing the reactivity of a metal species to elicit a favorable biological response, or passivating the reactivity of a metal species to prevent deleterious reactivity. The systemic administration of metal chelating agents, however, raises safety concerns due to the potential risks of indiscriminate extraction of metals from critical metalloproteins and inhibition of metalloenzymes. One can estimate that chelators capable of complexing metal ions with dissociation constants in the sub-micromolar range are thermodynamically capable of extracting metal ions from some metalloproteins and disrupting regular function. Such dissociation constants are easily attainable for multidentate chelators interacting with first-row d-block metal cations in relevant +1, +2, and +3 oxidation states. To overcome this challenge of indiscriminate metal chelation, we have pursued a prodrug strategy for chelating agents in which the resulting “prochelator” has negligible metal binding affinity until a specific stimulus generates a favorable metal binding site. The prochelator strategy enables conditional metal chelation to occur preferentially in spatial or temporal location initiated by disease- or therapy-associated stimuli, thereby minimizing off-target metal chelation. Our design of responsive prochelators encompasses three general approaches of activation: the “removal” approach operates by eliminating a masking group that blocks a potential metal chelation site to reveal the complete binding site under the desired conditions; the molecular “switch” approach involves a reversible conformational change between an inactive and active form of a chelator with differential metal binding affinity under specific conditions; while the “addition” approach adds a new ligand donor arm to the prochelator to constitute a complete metal chelation site. Adopting these approaches, we have created four categories of triggerable prochelators that respond to 1) reactive oxygen species, 2) light, 3) specific enzymes, and 4) biological regulatory events. This account highlights progress from our group on building prochelators that showcase these four categories of responsive metal chelating agents for manipulating cellular metals. The creation and chemical understanding of such stimulus-responsive prochelators enables exciting applications for understanding the cell biology of metals and for developing therapies based on metal-dependent processes in a variety of diseases.

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Prochelators triggered by hydrogen peroxide provide hexadentate iron coordination to impede oxidative stress

Cited by 29 publications

References 49 publications

A cell-permeable fluorescent prochelator responds to hydrogen peroxide and metal ions by decreasing fluorescence

A cell-permeable fluorescent prochelator responds to hydrogen peroxide and metal ions by decreasing fluorescence

Prochelator strategies for site-selective activation of metal chelators

Stimulus-Responsive Prochelators for Manipulating Cellular Metals

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