Deferasirox Derivatives: Ligands for the Lanthanide Series.

Deferasirox is an FDA-approved iron chelator used in the treatment of iron toxicity. In this work, we report the use of several deferasirox derivatives as lanthanide chelators. Solid-state structural studies of three representative trivalent lanthanide cations, La(III), Eu(III), and Lu(III), revealed the formation of 2:2 complexes in the solid state. A 1:1 stoichiometry dominates in DMSO solution, with Ka values of 472 ± 14, 477 ± 11, and 496 ± 15 M-1 being obtained in the case of these three cations, respectively. Under the conditions of competitive precipitation in the presence of triethylamine, high selectivity (up to 80%) for lutetium(III) was observed in competition with La(III), Ce(III), and Eu(III). Theoretical calculations provided support for the observed selective crystallization.

Metal Complexes and Nanoparticles for Photoacoustic Imaging.

Clinical imaging techniques are widely used to detect, locate, and track the growth or shrinkage of cancerous tumors. Although these techniques have shown impressive results, they often come with health risks due to the use of toxic contrast agents or ionizing radiation. To address these limitations, research efforts have been focused on the development of new imaging techniques. Among the emerging medicinal methods, photoacoustic imaging is receiving much attention. This method effectively combines the most important benefits of both ultrasound and fluorescence imaging, while minimizing their respective drawbacks via a light-in and ultrasound-out approach. This review article focuses on the fundamental concept, recent advances, and strategies for novel contrast agents based on molecular metal complexes or metallic nanoparticles for use in photoacoustic imaging.

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

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, ExNMe2 (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.

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

An increased demand for iron is a hallmark of cancer cells and is thought necessary to promote high cell proliferation, tumor progression and metastasis. This makes iron metabolism an attractive therapeutic target. Unfortunately, current iron-based therapeutic strategies often lack effectiveness and can elicit off-target toxicities. We report here a dual-therapeutic prodrug, DOXjade, that allows for iron chelation chemo-photothermal cancer therapy. This prodrug takes advantage of the clinically approved iron chelator deferasirox (ExJade®) and the topoisomerase 2 inhibitor, doxorubicin (DOX). Loading DOXjade onto ultrathin 2D Ti3C2 MXene nanosheets produces a construct, Ti 3 C 2 -PVP@DOXjade, that allows the iron chelation and chemotherapeutic functions of DOXjade to be photo-activated at the tumor sites, while potentiating a robust photothermal effect with photothermal conversion efficiencies of up to 40%. Antitumor mechanistic investigations reveal that upon activation, Ti 3 C 2 -PVP@DOXjade serves to promote apoptotic cell death and downregulate the iron depletion-induced iron transferrin receptor (TfR). A tumor pH-responsive iron chelation/photothermal/chemotherapy antitumor effect was achieved both in vitro and in vivo. The results of this study highlight what may constitute a promising iron chelation-based phototherapeutic approach to cancer therapy.

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

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 was found to have improved antiproliferative activity relative to 1. Fluorescent cell imaging revealed that compound 8 preferentially localises within the lysosome.

Deferasirox (ExJade): An FDA-Approved AIEgen Platform with Unique Photophysical Properties.

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.

Transition metal chelators, pro-chelators, and ionophores as small molecule cancer chemotherapeutic agents.

Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for improved chemotherapies. The primary challenges facing new cancer drugs include: (1) improving patient quality of life, (2) overcoming drug resistance and (3) lowering reoccurrence rates. Major drawbacks of current chemotherapeutics arise from poor selectivity towards cancer cells, dose limiting toxicities, compliance-reducing side effects, and an inability to address resistance mechanisms. Chemotherapeutics that fail to achieve complete eradication of the disease can also lead to relapse and promote treatment resistance. New strategies to overcome these drawbacks include the use of transition metal chelators and ionophores to alter selectively the concentrations of iron, copper, and zinc in cancer cells. A number of metal chelators have successfully demonstrated cytotoxicity and targeted activity against drug-resistant cancer cells; several have proved effective against cancer stem cells, a significant cause of tumour reoccurrence. However, problems with formulation and targeting have been noted. Recent efforts have thus focused on the design of pro-chelators, inactive versions of chelators that are designed to be activated in the tumour. This is an appealing strategy that may potentially increase efficacy towards cancer-resistant malignant cells. This Tutorial Review summarizes recent progress involving transition metal chelators, pro-chelators, and ionophores as potential cancer chemotherapeutics. We will focus on the reported agents that are able to coordinate iron, copper, and zinc.