Albumin Conjugates of Thiosemicarbazone and Imidazole‐2‐thione Prochelators: Iron Coordination and Antiproliferative Activity

Kerimoğlu

Ooi

et al. 2022

ACS Med. Chem. Lett.

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Glycoconjugation strategies in anticancer drug discovery exploit the high expression of glucose transporters in malignant cells to achieve preferential uptake and hence attractive pharmacological characteristics of increased therapeutic windows and decreased unwanted toxicity. Here we present the design of glycoconjugated prochelators of aroylhydrazone AH1, an antiproliferative scavenger that targets the increased iron demand of rapidly proliferating malignant cells. The constructs feature a monosaccharide (D-glucose, D-glucosamine, or glycolytic inhibitor 2-deoxy-D-glucose) connected at the C2 or C6 position via a short linker, which masks the chelator through a disulfide bond susceptible to intracellular reduction. Cellular assays showed that the glycoconjugates rely on the GLUT1 transporter for uptake, lead to intracellular iron deprivation, and present antiproliferative activity. Ectopic overexpression of GLUT1 in malignant and normal cells increased the uptake and toxicity of the glycoconjugated prochelators, demonstrating that these compounds are well suited for targeting cells overexpressing glucose transporters and therefore for selective iron sequestration in malignant cells.

supporting

confidence: 91%

mentioning

confidence: 83%

Aroylhydrazone Glycoconjugate Prochelators Exploit Glucose Transporter 1 (GLUT1) to Target Iron in Cancer Cells

Kerimoğlu

Ooi

et al. 2022

ACS Med. Chem. Lett.

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“…25−29 Upon cellular uptake, reduction of the disulfide bond releases a tridentate thiolate chelator that coordinates iron in mammalian cells. The disulfide linkage can also be employed to connect a biomolecule, such as a monosaccharide 30,31 or albumin, 32 to improve the cancer selectivity of the constructs and enhance their therapeutic window.…”

Section: ■ Introductionmentioning

confidence: 99%

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

Tomat

2023

J. Am. Chem. Soc.

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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.

“…Whereas thiosemicarbazone chelators derived from mercaptobenzaldehyde have so far resulted in low-spin ferric complexes, ,, the presence of a phenolic donor leads to a high-spin configuration in [Fe(STC4– H ) 2 ] + . Interestingly, the differences in ligand field are likely small, and chelators with similar binding units exhibit spin-crossover behavior. , …”

Section: Resultsmentioning

confidence: 99%

“…Alternatively, prochelators have been designed to act as substrates of specific enzymes, such as β-glucosidase and acetylcholinesterase (Figure b). We have developed disulfide-masked prochelators that are reductively activated in the presence of high concentrations of reduced glutathione (GSH) upon cellular uptake (Figure c). , Disulfide masks were employed in glucose , and albumin conjugates of improved selectivity and antiproliferative activity in cancer cells. Furthermore, we found that thiosemicarbazone prochelators affect the iron phenotype of tumor-associated macrophages and therefore have the potential to impact the tumor microenvironment. , …”

Section: Introductionmentioning

confidence: 99%

Thiol-Reactive Arylsulfonate Masks for Phenolate Donors in Antiproliferative Iron Prochelators

Tomat

2022

Inorg. Chem.

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Tridentate thiosemicarbazones, among several families of iron chelators, have shown promising results in anticancer drug discovery because they target the increased need for iron that characterizes malignant cells. Prochelation strategies, in which the chelator is released under specific conditions, have the potential to avoid off-target metal binding (for instance, in the bloodstream) and minimize unwanted side effects. We report a prochelation approach that employs arylsulfonate esters to mask the phenolate donor of salicylaldehyde-based chelators. The new prochelators liberate a tridentate thiosemicarbazone intracellularly upon reaction with abundant nucleophile glutathione (GSH). A 5bromo-substituted salicylaldehyde thiosemicarbazone (STC4) was selected for the chelator unit because of its antiproliferative activity at low micromolar levels in a panel of six cancer cell lines. The arylsulfonate prochelators were assessed in vitro with respect to their stability, ability to abolish metal binding, and reactivity in the presence of GSH. Cell-based assays indicated that the arylsulfonatemasked prochelators present higher antiproliferative activities relative to the parent compound after 24 h. The activation and release of the chelator intracellularly were corroborated by assays of cytosolic iron binding and iron supplementation effects as well as cell cycle analysis. This study introduces the 1,3,4-thiadiazole sulfonate moiety to mask the phenolate donor of an iron chelator and impart good solubility and stability to prochelator constructs. The reactivity of these systems can be tuned to release the chelator at high glutathione levels, as encountered in several cancer phenotypes.