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Synthesis and biological assessment of a ruthenium(II) cyclopentadienyl complex in breast cancer cells and on the development of zebrafish embryos

Golbaghi, Golara; Pitard, Irène; Lucas, Matthieu; Haghdoost, Mohammad Mehdi; Lopez de los Santos, Yossef; Doucet, Nicolas ORCID logoORCID: https://orcid.org/0000-0002-1952-9380; Patten, Shunmoogum A.; Sanderson, J. Thomas ORCID logoORCID: https://orcid.org/0000-0002-3190-2811 et Castonguay, Annie ORCID logoORCID: https://orcid.org/0000-0001-5705-6353 (2020). Synthesis and biological assessment of a ruthenium(II) cyclopentadienyl complex in breast cancer cells and on the development of zebrafish embryos European Journal of Medicinal Chemistry , vol. 188 , nº 112030. pp. 1-11. DOI: 10.1016/j.ejmech.2019.112030.

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Résumé

Ruthenium-based complexes currently attract great attention as they hold promise to replace platinum-based drugs as a first line cancer treatment. Whereas ruthenium arene complexes are some of the most studied species for their potential anticancer properties, other types of ruthenium complexes have been overlooked for this purpose. Here, we report the synthesis and characterization of Ru(II) cyclopentadienyl (Cp), Ru(II) cyclooctadienyl (COD) and Ru(III) complexes bearing anastrozole or letrozole ligands, third-generation aromatase inhibitors currently used for the treatment of estrogen receptor positive (ER +) breast cancer. Among these complexes, Ru(II)Cp 2 was the only one that displayed a high stability in DMSO and in cell culture media and consequently, the only complex for which the in vitro and in vivo biological activities were investigated. Unlike anastrozole alone, complex 2 was considerably cytotoxic in vitro (IC50 values < 1 muM) in human ER + breast cancer (T47D and MCF7), triple negative breast cancer (TNBC) (MBA-MB-231), and in adrenocortical carcinoma (H295R) cells. Theoretical (docking simulation) and experimental (aromatase catalytic activity) studies suggested that an interaction between 2 and the aromatase enzyme was not likely to occur and that the bulkiness of the PPh3 ligands could be an important factor preventing the complex to reach the active site of the enzyme. Exposure of zebrafish embryos to complex 2 at concentrations around its in vitro cytotoxicity IC50 value (0.1-1 muM) did not lead to noticeable signs of toxicity over 96 h, making it a suitable candidate for further in vivo investigations. This study confirms the potential of Ru(II)Cp complexes for breasts cancer therapy, more specifically against TNBCs that are usually not responsive to currently used chemotherapeutic agents.

Type de document: Article
Mots-clés libres: Aromatase inhibitor; Breast cancer therapy; Estrogen receptor positive breast cancer; Ruthenium complex; Triple negative breast cancer; Zebrafish
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 15 juill. 2021 14:41
Dernière modification: 15 févr. 2022 15:34
URI: https://espace.inrs.ca/id/eprint/11592

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