Anticancer Aminoferrocene Derivatives Inducing Production of Mitochondrial Reactive Oxygen Species

Özkan, Hülya Gizem; Thakor, V. M.; Xu, Hong‐Gui; Bila, Galyna; Bilyy, Rostyslav; Bida, Daria; Mougiakakos, Dimitrios; Tietze, Rainer; Mokhir, Andriy

doi:10.1002/chem.202104420

Cited by 8 publications

(7 citation statements)

References 28 publications

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“…We detected no signs of tumors, indicating that these animals were completely cured (Figure S62, Supporting Information). This is an exciting result, which we have previously never observed for other Fe-containing drugs. , Due to the excellent performance in the standard tumor model, we have also investigated its effects in the second, more challenging NK/Ly model, in which the cancer cells grow in the abdomen as ascites. This cancer is very aggressive, and untreated animals have a half-life of only 18 days.…”

Section: Resultsmentioning

confidence: 99%

3D-Shaped Binders of Unfolded Proteins Inducing Cancer Cell-Specific Endoplasmic Reticulum Stress In Vitro and In Vivo

Klemt,

Varzatskii,

Selin

et al. 2023

J. Am. Chem. Soc.

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The amount of unfolded proteins is increased in cancer cells, leading to endoplasmic reticulum (ER) stress. Therefore, cancer cells are sensitive to drugs capable of further enhancing ER stress. Examples of such drugs include the clinically approved proteosome inhibitors bortezomib and carfilzomib. Unfortunately, the known ER stress inducers exhibit dose-limiting side effects that justify the search for better, more cancer-specific drugs of this type. Herein, we report on FeC 2, which binds to unfolded proteins prevents their further processing, thereby leading to ER stress and ROS increase in cancer cells, but not in normal cells. FeC 2 exhibits low micromolar toxicity toward human acute promyelocytic leukemia HL-60, Burkitt’s lymphoma BL-2, T-cell leukemia Jurkat, ovarian carcinoma A2780, lung cancer SK-MES-1, and murine lung cancer LLC1 cells. Due to the cancer-specific mode of action, 2 is not toxic in vivo up to the dose of 147 mg/kg, does not affect normal blood and bone marrow cells at the therapeutically active dose, but strongly suppresses both primary tumor growth (confirmed in Nemeth-Kellner lymphoma and LLC1 lung cancer models of murine tumor) and spreading of metastases (LLC1).

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Section: Resultsmentioning

confidence: 99%

3D-Shaped Binders of Unfolded Proteins Inducing Cancer Cell-Specific Endoplasmic Reticulum Stress In Vitro and In Vivo

Klemt,

Varzatskii,

Selin

et al. 2023

J. Am. Chem. Soc.

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“…The ascites was isolated from the peritoneal cavity of mice with a syringe. This cellular suspension was then centrifuged at 1500 g to separate the cells and acellular supernatant, which was referred to as ascites fluid . After sedimentation, the cells were washed twice in PBS and used for analysis, while the ascites fluid was dissolved to 50% v / v in PBS due to the technical need for equalizing the volume in all samples.…”

Section: Methodsmentioning

confidence: 99%

“…This cellular suspension was then centrifuged at 1500g to separate the cells and acellular supernatant, which was referred to as ascites fluid. 39 After sedimentation, the cells were washed twice in PBS and used for analysis, while the ascites fluid was dissolved to 50% v/v in PBS due to the technical need for equalizing the volume in all samples. Additionally, some wells were supplemented with a protease inhibitor cocktail at a final concentration of 0.5% (Sigma-Aldrich P8340).…”

Section: Fluorescence Of Squaraine Dyes Upon An Interaction With Biol...mentioning

confidence: 99%

Photophysical Characterization and Biointeractions of NIR Squaraine Dyes for in Vitro and in Vivo Bioimaging

Mavileti,

Bila,

Utka

et al. 2023

ACS Appl. Bio Mater.

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The increasing demand for reliable near-infrared (NIR) probes exhibiting enduring fluorescence in living systems and facile compatibility with biomolecules such as peptides, antibodies or proteins is driven by the increasing use of NIR imaging in clinical diagnostics. To address this demand, a series of carboxy-functionalized unsymmetrical squaraine dyes (SQ-27, SQ-212, and SQ-215) along with non-carboxy-functionalized SQ-218 absorbing and emitting in the NIR wavelength range were designed and synthesized followed by photophysical characterization. This study focused on the impact of structural variations in the alkyl chain length, carboxy functionality positioning, and spacer chain length on dye aggregation and interaction with bovine serum albumin (BSA) as a model protein. In phosphate buffer (PB), the absorption intensity of the dyes markedly decreased accompanied by pronounced shoulders indicative of dye aggregation, and complete fluorescence quenching was seen in contrast to organic solvents. However, in the presence of BSA in PB, there was a enhancement in absorption intensity while regaining the fluorescence coupled with a remarkable increase in the intensity with increasing BSA concentrations, signifying the impact of dye−BSA interactions on preventing aggregation. Further analysis of Job's plot unveiled a 2:1 interaction ratio between BSA and all dyes, while the binding studies revealed a robust binding affinity (K a ) in the order of 10 7 /mol. SQ-212 and SQ-215 were further tested for their in vitro and in vivo imaging capabilities. Notably, SQ-212 demonstrated nonpermeability to cells, while SQ-215 exhibited easy penetration and prominent cytoplasmic localization in in vitro studies. Injection of the dyes into laboratory mice showcased their efficacy in visualization, displaying stable and intense fluorescence in tissues without toxicity, organ damage, or behavioral changes. Thus, SQ-212 and SQ-215 are promising candidates for imaging applications, holding potential for noninvasive cellular and diagnostic imaging as well as biomarker detection when coupled with specific vectors in living systems.

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“…Ferrocene-Capped Tripeptides 23-30 [35] Previous observations prompted us to investigate the use of ferrocene as a CD probe for the detection of screw sense preferences of short peptide sequences, for which we synthesized all eight stereoisomers of Boc-Pro-Pro-Ala-NH-Fn (23)(24)(25)(26)(27)(28)(29)(30) [35]. This investigation was inspired by early work by Toniolo [106] and his p-bromobenzamido chromophore and Clayden's dibenzazepinylurea [107], which were used as N-terminally covalently bound CD probes for determination and quantification of the screw sense preferences of peptide sequences.…”

Section: C-terminalmentioning

confidence: 99%

“…N-alkylaminoferrocene-based prodrugs, activated under cancerspecific conditions, i.e., a high ROS concentration, were able to reduce the mitochondrial membrane potential, but also showed low efficacy and high toxicity [21][22][23]. Structural optimization led to aminoferrocene derivatives that are able to generate mitochondrial ROSs only in cancer cells, and therefore have anticancer activity in vivo [24]. It has been shown that the self-immolative amphiphilic poly(ferrocenes) containing aminoferrocene side chains are triggered by acidic tumor conditions; the aminoferrocene moiety reacts to give Fe 2+ , which can catalyze the conversion of intracellular H 2 O 2 to highly reactive ˙OH, leading to the oxidative stress of tumor cells [25].…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in the Field of Amino Acid-Conjugated Aminoferrocenes—A Personal Perspective

Čakić Semenčić,

Kovačević,

Barišić

2024

IJMS

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The development of turn-based inhibitors of protein–protein interactions has attracted considerable attention in medicinal chemistry. Our group has synthesized a series of peptides derived from an amino-functionalized ferrocene to investigate their potential to mimic protein turn structures. Detailed DFT and spectroscopic studies (IR, NMR, CD) have shown that, for peptides, the backbone chirality and bulkiness of the amino acid side chains determine the hydrogen-bond pattern, allowing tuning of the size of the preferred hydrogen-bonded ring in turn-folded structures. However, their biological potential is more dependent on their lipophilicity. In addition, our pioneering work on the chiroptical properties of aminoferrocene-containing peptides enables the correlation of their geometry with the sign of the CD signal in the absorption region of the ferrocene chromophore. These studies have opened up the possibility of using aminoferrocene and its derivatives as chirooptical probes for the determination of various chirality elements, such as the central chirality of amino acids and the helicity of peptide sequences.

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Anticancer Aminoferrocene Derivatives Inducing Production of Mitochondrial Reactive Oxygen Species

Cited by 8 publications

References 28 publications

3D-Shaped Binders of Unfolded Proteins Inducing Cancer Cell-Specific Endoplasmic Reticulum Stress In Vitro and In Vivo

3D-Shaped Binders of Unfolded Proteins Inducing Cancer Cell-Specific Endoplasmic Reticulum Stress In Vitro and In Vivo

Photophysical Characterization and Biointeractions of NIR Squaraine Dyes for in Vitro and in Vivo Bioimaging

Recent Advances in the Field of Amino Acid-Conjugated Aminoferrocenes—A Personal Perspective

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