Clawing back: broadening the notion of metal chelators in medicine

Franz, Katherine J.

doi:10.1016/j.cbpa.2012.12.021

Cited by 45 publications

(42 citation statements)

References 35 publications

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“…In fact, Na 2 EDTA was withdrawn from the market in 2008 because of safety concerns. Approximately one-third of human proteins are metalloproteins, and nonspecific chelation of essential cofactors could have significant biological effects (99). While pharmaceutical companies are unlikely to select EDTA for development as an MBL inhibitor, the concept of chelator fragments with improved specificity may still be worth attention.…”

Section: The Unique Challenge Of Class B Mbls; Closer Than We Think?mentioning

confidence: 99%

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Drawz

Papp-Wallace

Bonomo

2014

Antimicrob Agents Chemother

266

179

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As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing ␤-lactamase enzymes to this serious clinical problem. This review highlights recent advances in ␤-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the ␤-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new ␤-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner ␤-lactam and dosing regimens for these promising agents. This "renaissance" of ␤-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.

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Section: The Unique Challenge Of Class B Mbls; Closer Than We Think?mentioning

confidence: 99%

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Drawz

Papp-Wallace

Bonomo

2014

Antimicrob Agents Chemother

266

179

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“…The latter can be achieved with Fe chelators, i.e . agents that form redox-inactive complexes with Fe and block the Fe-dependent and site-specific production of hydroxyl radicals [11–13]. Fe chelators have been tested in numerous cardiovascular diseases [14, 15].…”

Section: Introductionmentioning

confidence: 99%

Comparison of various iron chelators and prochelators as protective agents against cardiomyocyte oxidative injury

Jansová¹,

Macháček²,

Wang³

et al. 2014

Free Radical Biology and Medicine

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Oxidative stress is a common denominator of numerous cardiovascular disorders. Free cellular iron catalyzes formation of highly toxic hydroxyl radicals and iron chelation may thus be an effective therapeutic approach. However, using classical iron chelators in diseases without iron overload poses risks that necessitate more advanced approaches, such as prochelators that are activated to chelate iron only under disease-specific oxidative stress conditions. In this study, three cell membrane-permeable iron chelators (clinically-used deferasirox and experimental SIH and HAPI) and five boronate-masked prochelator analogs were evaluated for their ability to protect cardiac cells against oxidative injury induced by hydrogen peroxide. Whereas the deferasirox-derived agents TIP and TRA-IMM displayed negligible protection and even considerable toxicity, aroylhydrazone prochelators BHAPI and BSIH-PD provided significant cytoprotection and displayed lower toxicity following prolonged cellular exposure compared to their parent chelators HAPI and SIH, respectively. Overall, the most favorable properties in terms of protective efficiency and low inherent cytotoxicity were observed with aroylhydrazone prochelator BSIH. BSIH efficiently protected both H9c2 rat cardiomyoblast-derived cells as well as isolated primary rat cardiomyocytes against hydrogen peroxide-induced mitochondrial and lysosomal dysregulation and cell death. At the same time, BSIH was non-toxic at concentrations up to its solubility limit (600 µM) and 72-hour incubation. Hence, BSIH merits further investigation for prevention and/or treatment of cardiovascular disorders associated with a known (or presumed) component of oxidative stress.

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“…The ability of such compounds to recruit metal cations in the biological milieu could not only modify on-target efficacy, but also affect intracellular metal homeostasis and introduce new reactivity (for instance, through the redox chemistry of metal complexes formed in situ). 2 These effects could lead to the repositioning of known drugs and/or to the identification of new therapeutic opportunities. Therefore, the potential for biological effects and/or polypharmacologic profiles involving metal coordination should be evaluated carefully.…”

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confidence: 99%