Cytotoxic BODIPY-Appended Half-Sandwich Iridium(III) Complex Forms Protein Adducts and Induces ER Stress

Ramos, Robin; Gilles, Jean-François; Morichon, Romain; Przybylski, Cédric; Caron, B.; Botuha, Candice; Karaı̈skou, Anthi; Salmain, Michèle; Sobczak-Thépot, Joëlle

doi:10.1021/acs.jmedchem.1c01335

Cited by 12 publications

(8 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The distribution of complex 6 inside the cells was investigated next. DNA ,, as well as the mitochondria, ,,,,,,, endoplasmic reticulum (ER), , or lysosomes , have been described to be targets of iridium cyclometalated complexes. The cells were incubated with the complex at 10 μM for 4 h at 37 °C to allow its maximum accumulation and the major cellular compartments (nuclear, membrane/particulate, cytosolic, and cytoskeletal) were isolated.…”

Section: Resultsmentioning

confidence: 99%

Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy

Gonzalo-Navarro,

Zafon,

Organero

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We have used the strategy of coordinating π-expansive ligands to increase the excited state lifetimes of Ir(III) half-sandwich complexes in order to facilitate the generation of 1 O 2 . We have obtained derivatives of formulas [Cp*Ir(C ∧ N)Cl] and [Cp*Ir-(C ∧ N)L]BF 4 with different degrees of π-expansion in the C ∧ N ligands. Complexes with the more π-expansive ligand are very effective photosensitizers with phototoxic indexes PI > 2000. Furthermore, PI values of 63 were achieved with red light. Timedependent density functional theory (TD-DFT) calculations nicely explain the effect of the π-expansion. The complexes produce reactive oxygen species (ROS) at the cellular level, causing mitochondrial membrane depolarization, cleavage of DNA, nicotinamide adenine dinucleotide (NADH) oxidation, as well as lysosomal damage. Consequently, cell death by apoptosis and secondary necrosis is activated. Thus, we describe the first class of halfsandwich iridium cyclometalated complexes active in PDT.

show abstract

Section: Resultsmentioning

confidence: 99%

Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy

Gonzalo-Navarro,

Zafon,

Organero

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…He et al introduced triphenylamine (TPA) and its derivatives into half-sandwich Ir III complexes, which endowed them with suitable fluorescence properties . These studies confirmed that the introduction of fluorescent molecules (rhodamine B, coumarin, triphenylamine, BODIPY, etc.) could endow half-sandwich Ir III complexes with suitable fluorescence through proper design; however, there have been few reports of complexes with excellent fluorescence properties and antitumor activity.…”

Section: Introductionmentioning

confidence: 89%

In Vitro and In Vivo Antitumor Assay of Mitochondrially Targeted Fluorescent Half-Sandwich Iridium(III) Pyridine Complexes

Wang

Liu

et al. 2023

Inorg. Chem.

View full text Add to dashboard Cite

Half-sandwich iridium(III) complexes show potential value in the anticancer field. However, complexes with favorable luminescence performance are rare, which limits further investigation of the anticancer mechanism. In this paper, 10 triphenylamine-modified fluorescent halfsandwich iridium(III) pyridine complexes {[(η 5 -Cp x )Ir(L)Cl 2 ]} (Ir1− Ir10) were prepared and showed potential antiproliferative activity, effectively inhibiting the migration of A549 cells. Ir6, showing the best activity among these complexes, exhibited excellent fluorescence performance (absolute fluorescence quantum yield of 15.17%) in solution. Laser confocal detection showed that Ir6 followed an energy-dependent cellular uptake mechanism, specifically accumulating in mitochondria (Pearson co-localization coefficient of 0.95). A Western blot assay further confirmed the existence of a mitochondrial apoptotic channel. Additionally, Ir6 could arrest the cell cycle at the G 2 /M phase, catalyze NADH oxidation, reduce the mitochondrial membrane potential, induce an increase in the level of intracellular reactive oxygen species, and exhibit a mechanism of oxidation. An in vivo antitumor assay confirmed that Ir6 can effectively inhibit tumor growth and is safer than cisplatin.

show abstract

“…Metallodrugs are emerging as alternative ER stress inducers. , Compared to organic drugs, they offer additional metal-centered reactivity for drug design including coordination chemistry, photo(redox) chemistry, and dark redox chemistry. The metallodrugs can trigger the ER stress via four distinct upstream events. , First, coordinatively unsaturated complexes (CUCs) form metal–biomolecule bonds, e.g., Pt 2+ in cisplatin binds N7 of purine residues in DNA, Au + complexes coordinate a selenocysteine residue in thioredoxin reductase, Ir 3+ half-sandwich complexes bind histidine and cysteine residues in proteins, and a Ru 3+ complex BOLD-100/KP1339 binds ribosomal proteins . Second, redox-active complexes induce the catalytic generation of reactive products via electron transfer either to or from intracellular substrates.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, in normal cells containing the low level of UPs, this equilibrium is shifted toward the unbound UPs, which can be normally processed. Thus, the optimized BUP will be toxic to cancer cells, but not affect normal cells (Figure B), thereby solving the problem of side effects of common ER stress inducers. – …”

Section: Introductionmentioning

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.

View full text Add to dashboard Cite

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).

show abstract

Cytotoxic BODIPY-Appended Half-Sandwich Iridium(III) Complex Forms Protein Adducts and Induces ER Stress

Cited by 12 publications

References 51 publications

Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy

Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy

In Vitro and In Vivo Antitumor Assay of Mitochondrially Targeted Fluorescent Half-Sandwich Iridium(III) Pyridine Complexes

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

Contact Info

Product

Resources

About