<i>In vitro</i> studies of deferasirox derivatives as potential organelle-targeting traceable anti-cancer therapeutics

Steinbrueck, Axel; Sedgwick, Adam; Han, Hai-Hao; Zhao, Michael; Sen, Sajal; Huang, Dan-Ying; Zang, Yi; Li, Jia; He, Xiao‐Peng; Sessler, Jonathan L.

doi:10.1039/d0cc08156f

Cited by 11 publications

(10 citation statements)

References 28 publications

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“…While not a proof, this poor solubility could account for the minimal cytotoxicities seen toward HeLa cells (24-h incubation, see Supporting Information Figure S19). Conversely, this finding leads us to suggest that the good 24-h cytotoxicity seen for a previously reported derivative, Ex-DMED , in human cell lines is due to its relatively greater solubility and cellular permeability with respect to the new derivatives reported in this study. On the other hand, the lack of apparent cytotoxicity led us to consider that the present deferasirox systems might have a role to play in bacterial imaging.…”

Section: Results and Discussionmentioning

confidence: 47%

“…Because of the pathological role of Fe(II/III) in several disease states, iron chelators have gained increasing attention for use as potential therapeutics. − In particular, deferasirox, an FDA-approved iron chelator used for the treatment of iron overload, has recently been shown to have anticancer and antimicrobial activity. − However, its nonfluorescent nature means that secondary biological assays are required to determine its cellular uptake, localization, and pharmacokinetic properties . Recent efforts from our group led to the identification of the deferasirox scaffold as an aggregation-induced emission (AIE) platform .…”

Section: Introductionmentioning

confidence: 99%

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Tuning the Solid- and Solution-State Fluorescence of the Iron-Chelator Deferasirox

Sedgwick

Mangel

et al. 2022

J. Am. Chem. Soc.

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Deferasirox, an FDA-approved iron chelator, has gained increasing attention for use in anticancer and antimicrobial applications. Recent efforts by our group led to the identification of this core as an easy-to-visualize aggregation-induced emission platform, or AIEgen, that provides a therapeutic effect equivalent to deferasirox (J. Am. Chem. Soc. 2021, 143, 3, 1278–1283). However, the emission wavelength of the first-generation system overlapped with that of Syto9, a green emissive dye used to indicate live cells. Here, we report a library of deferasirox derivatives with various fluorescence emission profiles designed to overcome this limitation. We propose referring to systems that show promise as both therapeutic and optical imaging agents as “illuminoceuticals”. The color differences between the derivatives were observable to the unaided eye (solid- and solution-state) and were in accord with the Commission Internationale de L’Eclairage (CIE) chromaticity diagram 1913. Each fluorescent derivative successfully imaged the respective spherical and rod shapes of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. They also displayed iron-dependent antibiotic activity. Three derivatives, ExNMe 2 (3), ExTrisT (11), and ExDCM (13), display emission features that are sufficiently distinct so as to permit the multiplex (triplex) imaging of both MRSA and P. aeruginosa via stimulated emission depletion microscopy. The present deferasirox derivatives allowed for the construction of a multi-fluorophore sensor array. This array enabled the successful discrimination between Gram-positive/Gram-negative and drug-sensitive/drug-resistant bacteria. Antibiotic sensitivity and drug-resistant mutants from clinically isolated strains could also be identified and differentiated.

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Section: Results and Discussionmentioning

confidence: 47%

Section: Introductionmentioning

confidence: 99%

Tuning the Solid- and Solution-State Fluorescence of the Iron-Chelator Deferasirox

Sedgwick

Mangel

et al. 2022

J. Am. Chem. Soc.

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“…This system was based on deferasirox (ExJade) an FDAapproved iron chelator, which is used to treat patients with iron overload. Owing to the pathological role of iron, this system enabled the tracking and detection of disease-based biomarkers while providing inherent therapeutic properties (Steinbrueck et al, 2021;Steinbrueck et al, 2020).…”

Section: Current State Of the Artmentioning

confidence: 99%

Fluorescent Chemosensors for Ion and Molecule Recognition: The Next Chapter

et al. 2021

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Over the past 30 years fluorescent chemosensors have evolved to incorporate many optical-based modalities and strategies. In this perspective we seek to highlight the current state of the art as well as provide our viewpoint on the most significant future challenges remaining in the area. To underscore current trends in the field and to facilitate understanding of the area, we provide the reader with appropriate contemporary examples. We then conclude with our thoughts on the most probable directions that chemosensor development will take in the not-too-distant future.

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“…One notable system of interest in this context is the FDA-approved iron chelating agent deferasirox (ExJade®, Scheme 1 ) [ 12 , 13 ], which has been shown to exert inhibitory effects towards cancer cells in vitro and in vivo models derived from human liver, lung and pancreatic cells. Promising preliminary success in the treatment of a patient with acute myelogenous leukemia has also been reported [ [14] , [15] , [16] ]. Unfortunately, dose-dependent toxicity and non-targeting issues constitute roadblocks in the clinical development of deferasirox for cancer-related indications.…”

Section: Introductionmentioning

confidence: 99%

In vitro studies of deferasirox derivatives as potential organelle-targeting traceable anti-cancer therapeutics

Abstract: We report here strategic functionalization of the FDA approved chelator deferasirox (1) in an effort to produce organelle-targeting iron chelators with enhanced activity against A549 lung cancer cells. Derivative 8...

Cited by 11 publications

References 28 publications

Tuning the Solid- and Solution-State Fluorescence of the Iron-Chelator Deferasirox

Tuning the Solid- and Solution-State Fluorescence of the Iron-Chelator Deferasirox

Fluorescent Chemosensors for Ion and Molecule Recognition: The Next Chapter

2D-ultrathin MXene/DOXjade platform for iron chelation chemo-photothermal therapy

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