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.
Deferasirox,
ExJade, is an FDA-approved iron chelator used for
the treatment of iron overload. In this work, we report several fluorescent
deferasirox derivatives that display unique photophysical properties,
i.e., aggregation-induced emission (AIE), excited state intramolecular
proton transfer, charge transfer, and through-bond and through-space
conjugation characteristics in aqueous media. Functionalization of
the phenol units on the deferasirox scaffold afforded the fluorescent
responsive pro-chelator ExPhos, which enabled the detection of the
disease-based biomarker alkaline phosphatase (ALP). The diagnostic
potential of these deferasirox derivatives was supported by bacterial
biofilm studies.
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.
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...
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