Targeting Iron in Colon Cancer via Glycoconjugation of Thiosemicarbazone Prochelators

The implication of iron in the pathophysiology of colorectal cancer is documented at both the biochemical and epidemiological levels. Iron chelators are therefore useful molecular tools for the study and potential treatment of this type of cancer characterized by high incidence and mortality rates. We report a novel prochelation strategy that utilizes a disulfide redox switch to connect a thiosemicarbazone iron-binding unit with carbohydrate moieties targeting the increased expression of glucose transporters in colorectal cancer cells. We synthesized three glycoconjugates (GA2TC4, G6TC4, and M6TC4) with different connectivity and/or carbohydrate moieties, as well as an aglycone analog (ATC4). The sugar conjugates present increased solubility in neutral aqueous solutions, and the ester-linked conjugates M6TC4 and G6TC4 compete as effectively as d-glucose for transporter-mediated cellular uptake. The glycoconjugates show improved selectivity compared to the aglycone analog and are 6–11 times more toxic in Caco-2 colorectal adenocarcinoma cells than in normal CCD18-co colon fibroblasts

Ratiometric and Intensity-Based Zinc Sensors Built on Rhodol and Rhodamine Platforms

A xanthene-forming condensation reaction yields rhodol and rhodamine dyes carrying a zinc-binding ligand that includes the aniline-type nitrogen donor of the fluorophores. Upon zinc coordination in neutral aqueous solution, rhodol RF3 behaves as a ratiometric sensor, and rhodamine RA1 acts as a turn-off intensity-based indicator. Both fluorescent compounds bind the divalent zinc cation with micromolar affinity

Design of Tetrazolium Cations for the Release of Antiproliferative Formazan Chelators in Mammalian Cells

Cancer cells generally present a higher demand for iron, which plays crucial roles in tumor progression and metastasis. This iron addiction provides opportunities to develop broad spectrum anticancer drugs that target iron metabolism. In this context, prochelation approaches are investigated to release metal-binding compounds under specific conditions, thereby limiting off-target toxicity. Here, we demonstrate a prochelation strategy inspired by the bioreduction of tetrazolium cations widely employed to assess the viability of mammalian cells. We designed a series of tetrazolium-based compounds for the intracellular release of metal-binding formazan ligands. The combination of reduction potentials appropriate for intracellular reduction and an N-pyridyl donor on the formazan scaffold led to two effective prochelators. The reduced formazans bind as tridentate ligands and stabilize low-spin Fe­(II) centers in complexes of 2:1 ligand-to-metal stoichiometry. The tetrazolium salts are stable in blood serum for over 24 h, and antiproliferative activities at micromolar levels were recorded in a panel of cancer cell lines. Additional assays confirmed the intracellular activation of the prochelators and their ability to affect cell cycle progression, induce apoptotic death, and interfere with iron availability. Demonstrating the role of iron in their intracellular effects, the prochelators impacted the expression levels of key iron regulators (i.e., transferrin receptor 1 and ferritin), and iron supplementation mitigated their cytotoxicity. Overall, this work introduces the tetrazolium core as a platform to build prochelators that can be tuned for activation in the reducing environment of cancer cells and produce antiproliferative formazan chelators that interfere with cellular iron homeostasis

Positive Homotropic Allosteric Binding of Silver(I) Cations in a Schiff Base Oligopyrrolic Macrocycle

The binuclear silver(I) complex of a Schiff base oligopyrrolic macrocycle was prepared in high yield and fully characterized. UV−visible absorption and 1H NMR spectroscopic analyses reveal that coordination of Ag(I) cations is subject to a strong positive homotropic allosteric effect

Positive Homotropic Allosteric Binding of Silver(I) Cations in a Schiff Base Oligopyrrolic Macrocycle

The binuclear silver(I) complex of a Schiff base oligopyrrolic macrocycle was prepared in high yield and fully characterized. UV−visible absorption and 1H NMR spectroscopic analyses reveal that coordination of Ag(I) cations is subject to a strong positive homotropic allosteric effect

Organelle-Specific Zinc Detection Using Zinpyr-Labeled Fusion Proteins in Live Cells

Organelle-Specific Zinc Detection Using Zinpyr-Labeled Fusion Proteins in Live Cell

Binuclear Fluoro-Bridged Zinc and Cadmium Complexes of a Schiff Base Expanded Porphyrin: Fluoride Abstraction from the Tetrafluoroborate Anion

Reactions of the Schiff base oligopyrrolic octaazamacrocycle 1 with BF4- salts of divalent zinc and cadmium result in fluoride anion abstraction and the formation of difluoride-bridged metal complexes. X-ray diffraction analyses provide support for the notion that hydrogen-bonding interactions, involving the N−H groups of the macrocycle and the coordinated fluoride ions, play an important role in stabilizing these new complexes

Binuclear Fluoro-Bridged Zinc and Cadmium Complexes of a Schiff Base Expanded Porphyrin: Fluoride Abstraction from the Tetrafluoroborate Anion

Reactions of the Schiff base oligopyrrolic octaazamacrocycle 1 with BF4- salts of divalent zinc and cadmium result in fluoride anion abstraction and the formation of difluoride-bridged metal complexes. X-ray diffraction analyses provide support for the notion that hydrogen-bonding interactions, involving the N−H groups of the macrocycle and the coordinated fluoride ions, play an important role in stabilizing these new complexes

Paramagnetism and Fluorescence of Zinc(II) Tripyrrindione: A Luminescent Radical Based on a Redox-Active Biopyrrin

The ability of bilins and other biopyrrins to form fluorescent zinc complexes has been known for more than a century; however, the exact identity of the emissive species remains uncertain in many cases. Herein, we characterize the hitherto elusive zinc complex of tripyrrin-1,14-dione, an analogue of several orange urinary pigments. As previously observed for its Pd­(II), Cu­(II), and Ni­(II) complexes, tripyrrindione binds Zn­(II) as a dianionic radical and forms a paramagnetic complex carrying an unpaired electron on the ligand π-system. This species is stable at room temperature and undergoes quasi-reversible ligand-based redox chemistry. Although the complex is isolated as a coordination dimer in the solid state, optical absorption and electron paramagnetic resonance spectroscopic studies indicate that the monomer is prevalent in a tetrahydrofuran solution. The paramagnetic Zn­(II) tripyrrindione complex is brightly fluorescent (λabs = 599 nm, λem = 644 nm, ΦF = 0.23 in THF), and its study provides a molecular basis for the observation, made over several decades since the 1930s, of fluorescent behavior of tripyrrindione pigments in the presence of zinc salts. The zinc-bound tripyrrindione radical is thus a new addition to the limited number of stable radicals that are fluorescent at room temperature

Prodigiosin Analogue Designed for Metal Coordination: Stable Zinc and Copper Pyrrolyldipyrrins

The pyrrolyldipyrrin motif is found in several naturally occurring prodigiosin pigments. The potential roles of the interactions of prodigiosins with transition metals and the properties of metal-bound pyrrolyldipyrrins, however, have been difficult to assess because of the very limited number of well-characterized stable complexes. Here, we show that the introduction of a <i>meso</i>-aryl substituent and an ethyl ester group during the sequential assembly of the three heterocycles affords a pyrrolyldipyrrin of enhanced coordinating abilities when compared to that of natural prodigiosins. UV–visible absorption studies indicate that this ligand promptly binds Zn­(II) ions with 2:1 ligand-to-metal stoichiometry and Cu­(II) ions with 1:1 stoichiometry. Notably, no addition of base is required for the formation of the resulting stable complexes. The crystal structures reveal that whereas the tetrahedral zinc center engages two nitrogen donors on each ligand, the pseudosquare planar copper complex features coordination of all three pyrrolic nitrogen atoms and employs the ester group as a neutral ligand. This first example of coordination of a redox-active transition metal within a fully conjugated pyrrolyldipyrrin framework was investigated spectroscopically by electron paramagnetic resonance to show that the 1:1 metal-to-ligand ratio found in the crystal structure is also maintained in solution