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Not AvailabCopper and iron are redox-active essential metals that are disproportionately required by cancer cells to sustain proliferation, survival, and metastasis. Their intertwined biology represents a universal metabolic vulnerability that could be therapeutically exploited. Here, we investigate the possibility of a dual-metal targeting strategy using deferasirox (Def), a clinically approved iron chelator, and its titanium(IV) complex, Ti(Def)₂, to disrupt Cu and Fe homeostasis through intracellular transmetalation. Solution speciation and metal competition studies reveal an unexpectedly strong affinity for Cu(II) that exceeds predictions based on HSAB theory. UV Vis, EPR, and mass spectrometric analyses suggest that Cu(II) Def species predominate as square-planar monomers at low micromolar concentrations and undergo salt-dependent dimerization at higher concentrations, supported by X-ray diffraction of the dimeric [Cu(Def)(py)]₂ complex. Cell-based studies indicate that intracellular Cu(II) binding by Def may contribute to the apoptotic cytotoxicity of Ti(Def)₂. In A549 lung cancer cells, transmetalation with labile Cu(II) complements previously reported Fe(III) transmetalation, generating redox-active Cu(II) Def species (Ec = 0.0398 V) alongside redox-active Fe(III) Def species. In the reducing intracellular environment, these complexes can undergo reductive dissociation, increasing cellular Cu(I) and Fe(II) levels and likely perturb metal homeostasis. Ti(Def)₂ itself is redox inert, implicating Cu- and Fe–Def intermediates as the primary sources of reactive oxygen species, including superoxide, leading to oxidative stress and apoptotic cell death. Minimal off-target transmetalation with serum Cu carrier proteins supports the intracellular selectivity of this approach. Together, these findings establish the framework for Cu and Fe transmetalation-driven redox dysregulation as an anticancer strategy. 

Not AvChelation therapy has long been recognized for its success in treating heavy metal poisoning and iron overload disorders. Building on this foundation, drug repurposing of FDA-approved iron chelators for anticancer therapy has been extensively explored, alongside the development of novel agents such as the promising triapine. Current research increasingly targets the essential metals iron, copper, and zinc in oncology, with a focus on chelators that actively modulate the biochemical effects of these metals rather than functioning as ionophores. This review highlights recent advances in refining chelation strategies to enhance cytotoxic potency and tumor specificity, including approaches that tune metal redox activity, synergize with platinum(II)-based drugs, incorporate nanoparticulate delivery systems, leverage metal-driven immunostimulation, and combine with established or emerging therapies. By assessing the successes and limitations of recent studies and surveying relevant human clinical trials, we evaluate the feasibility of integrating chelation therapy into clinical oncology. Evidence suggests that chelation is most effective when combined with other treatment modalities, offering potential synergistic benefits in cancer management.ailable 

Deferasirox (Def), an orally administered iron‐chelating drug, has drawn significant interest in repurposing for anticancer application due to the elevated Fe demand by cancer cells. But there are also concerns about its severe off target health effects. Herein Cu(II) binding is studied as a potential off target interaction. The aqueous solution stability and speciation of the ternary complex Cu(Def)(pyridine) was studied by UV‐Vis and EPR spectroscopy, ESI‐mass spectrometry, and cyclic voltammetry under physiologically relevant conditions. The complex is observed to be a redox active, mononuclear Cu(II) complex in square planar geometry. UV‐Vis spectroscopy demonstrates that at pH 7.4 the complex is quite stable (ϵ337nm =10,820 M^−1cm^−1) with a log K=16.65±0.1. Cu scavenging from the Cu transporters ceruloplasmin and albumin was also studied. Def does not inhibit ceruloplasmin activity but forms a ternary Cu(II) complex at the bovine serum albumin ATCUN site. Cu(Def)(py) displays potent but nonselective cytotoxicity against A549 cancer and MRC‐5 noncancer lung cells but the potency of the ternary protein complex was more moderate. This work elucidates potential Def toxicity from Cu complexation in the body but also cytotoxic synergy between the metal and chelator that informs on new drug design directions. 

Titanium(IV) compounds are promising anticancer agents, but their development is hindered by poor aqueous stability and/or inefficient cellular delivery. This study compares two Ti(IV) compounds with contrasting properties: titanocene‐dichloride (TDC), which rapidly hydrolyzes at physiological pH, and the more stable chelated complex [Ti(deferasirox)2] (Ti(Def)2, which has limited cellular uptake. To overcome these limitations, passive and active cell targeting drug delivery systems were explored. TDC was intercalated into layered zirconium phosphate nanoparticles (TDC@ZrP), passive carriers enabling acid‐triggered release under lysosomal environments. Bovine serum albumin (BSA) binding and conjugation to receptor‐targeted deferasirox–peptide ligands were used as active carriers. TDC@ZrP increased intracellular Ti(IV) uptake by ∼ 26‐fold relative to free TDC, yet without an increase in antiproliferative activity. Similarly, stabilization with BSA enhanced solution stability but not cytotoxicity. In contrast, Ti(Def)2 showed transporter‐dependent activity. While albumin binding reduced its efficacy, conjugation to a transferrin receptor‐1 targeting peptide significantly enhanced titanium uptake and cytotoxicity. Targeting the neurokinin‐1 receptor had minimal effect, consistent with low receptor expression. Overall, these findings demonstrate that ligand identity is critical, as deferasirox not only controls Ti(IV) release but also contributes to cytotoxicity, highlighting the importance of metal–ligand design in improving anticancer performance. 

Breast cancer is currently the most commonlydiagnosed cancer, with 287,850 new cases estimated for 2022 asreported by the American Cancer Society. Therefore, finding aneffective treatment for this disease is imperative. Chalcones are α,β-unsaturated systems found in nature. These compounds haveshown a wide array of biological activities, making them popularsynthetic targets. Chalcones consist of two aromatic substituentsconnected by an enone bridge; this arrangement allows for a largenumber of derivatives. Given the biological relevance of thesecompounds, novel ferrocene-heterocycle-containing chalcones weresynthesized and characterized based on a hybrid drug designapproach. These heterocycles included thiophene, pyrimidine,thiazolyl, and indole groups. Fourteen novel heterocyclic ferrocenyl chalcones were synthesized and characterized. Herein, we alsoreport their cytotoxicity against triple-negative breast cancer cell lines MDA-MB-231 and 4T1 and the noncancer lung cell lineMRC-5. System 3 ferrocenyl chalcones displayed superior anticancer properties compared to their system 1 analogues. System 3chalcones bearing five-membered heterocyclic substituents (thiophene, pyrazole, pyrrole, and pyrimidine) were the most activetoward the MDA-MB-231 cancer cell line with IC50 values from 6.59 to 12.51 μM. Cytotoxicity of the evaluated compounds in the4T1 cell line exhibited IC50 values from 13.23 to 213.7 μM. System 3 pyrazole chalcone had consistent toxicity toward both cell lines(IC50 ∼ 13 μM) as well as promising selectivity relative to the noncancer MRC-5 control. Antioxidant activity was also evaluated,where, contrary to anticancer capabilities, system 1 ferrocenyl chalcones were superior to their system 3 analogues. Antioxidantactivity comparable to that of ascorbic acid was observed for thiophene-bearing ferrocenyl chalcone with EC50 = 31 μM. 

The discovery of regulated cell death (RCD) revolutionized chemotherapy. With caspase-dependent apoptosis initially being thought to be the only form of RCD, many drug development strategies aimed to synthesize compounds that turn on this kind of cell death. While yielding a variety of drugs, this approach is limited, given the acquired resistance of cancers to these drugs and the lack of specificity of the drugs for targeting cancer cells alone. The discovery of non-apoptotic forms of RCD is leading to new avenues for drug design. Evidence shows that ferroptosis, a relatively recently discovered iron-based cell death pathway, has therapeutic potential for anticancer application. Recent studies point to the interrelationship between iron and other essential metals, copper and zinc, and the disturbance of their respective homeostasis as critical to the onset of ferroptosis. Other studies reveal that several coordination complexes of non-iron metals have the capacity to induce ferroptosis. This collective knowledge will be assessed to determine how chelation approaches and coordination chemistry can be engineered to program ferroptosis in chemotherapy. 

Due to the rapid mutation of pathogenic microorganisms, drug-resistant superbugs have evolved. Antimicrobial-resistant germs may share their resistance genes with other germs, making them untreatable. The search for more combative antibiotic compounds has led researchers to explore metal-based strategies centered on perturbing the bioavailability of essential metals in microbes and examining the therapeutic potential of metal complexes. Given the limited knowledge on the application of titanium(IV), in this work, eight Ti(IV) complexes and some of their corresponding ligands were screened by the Community for Open Antimicrobial Drug Discovery for antimicrobial activity. The compounds were selected for evaluation because of their low cytotoxic/antiproliferative behavior against a human non-cancer cell line. At pH 7.4, these compounds vary in terms of their solution stability and ligand exchange lability; therefore, an assessment of their solution behavior provides some insight regarding the importance of the identity of the metal compound to the antimicrobial therapeutic potential. Only one compound, Ti(deferasirox)2, exhibited promising inhibitory activity against the Gram-positive bacteria methicillin-resistant Staphylococcus aureus and minimal toxicity against human cells. The ability of this compound to undergo transmetalation with labile Fe(III) sources and, as a consequence, inhibit Fe bioavailability and ribonucleotide reductase is evaluated as a possible mechanism for its antibiotic effect. 

Classical antibacterial drugs were designed to target specific bacterial properties distinct from host human cells to maximize potency and selectivity. These designs were quite effective as they could be easily derivatized to bear next-generation drugs. However, the rapid mutation of bacteria and their associated acquired drug resistance have led to the rise of highly pathogenic superbug bacterial strains for which treatment with first line drugs is no match. More than ever, there is a dire need for antibacterial drug design that goes beyond conventional standards. Taking inspiration by the body’s innate immune response to employ its own supply of labile copper ions in a toxic attack against pathogenic bacteria, which have a very low Cu tolerance, this review article examines the feasibility of Cu-centric strategies for antibacterial preventative and therapeutic applications. Promising results are shown for the use of Cu-containing materials in the hospital setting to minimize patient bacterial infections. Studies directed at disrupting bacterial Cu regulatory pathways elucidate new drug targets that can enable toxic increase of Cu levels and perturb bacterial dependence on iron. Likewise, Cu intracellular chelation/prochelation strategies effectively induce bacterial Cu toxicity. Cu-based small molecules and nanoparticles demonstrate the importance of the Cu ions in their mechanism and display potential synergism with classical drugs. 

Titanium is one of the most abundant elements in the earth’s crust and while there are many examples of its bioactive properties and use by living organisms, there are few studies that have probed its biochemical reactivity in physiological environments. In the cosmetic industry, TiO2 nanoparticles are widely used. They are often incorporated in sunscreens as inorganic physical sun blockers, taking advantage of their semiconducting property, which facilitates absorbing ultraviolet (UV) radiation. Sunscreens are formulated to protect human skin from the redox activity of the TiO2 nanoparticles (NPs) and are mass-marketed as safe for people and the environment. By closely examining the biological use of TiO2 and the influence of biomolecules on its stability and solubility, we reassess the reactivity of the material in the presence and absence of UV energy. We also consider the alarming impact that TiO2 NP seepage into bodies of water can cause to the environment and aquatic life, and the effect that it can have on human skin and health, in general, especially if it penetrates into the human body and the bloodstream.