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oai:riubu.ubu.es:10259/62532024-07-25T07:33:04Zcom_10259_4363com_10259_5086com_10259_2604com_10259_4365com_10259_6256com_10259_9476com_10259.4_106col_10259_9477col_10259_4366col_10259_6257col_10259_4364

Distinct mechanism of action for antitumoral neutral cyclometalated Pt(II)-complexes bearing antifungal imidazolyl-based drugs Fernández Pampín, Natalia Vaquero Gutiérrez, Mónica Gil Antón, Tania Espino Ordóñez, Gustavo Fernández Zoppino, Darío García Ruiz, Begoña Busto Vázquez, Natalia Cyclometalated platinum(II) complexes Clotrimazole Bifonazole Reactive oxygen species (ROS) Antitumoral Química inorgánica Bioquímica Chemistry, Inorganic Biochemistry Three neutral Pt(II) complexes containing 1-Methylimidazole and the antifungal imidazolyl drugs Clotrimazole and Bifonazole have been prepared. The general formula of the new derivatives is [Pt(κ2-(C^N)Cl(L)], where C^N stands for ppy = 2-phenylpyridinate, and L = 1-Methylimidazole (MeIm) for [Pt-MeIm]; L = Clotrimazole (CTZ) for [Pt-CTZ] and L = Bifonazole (BFZ) for [Pt-BFZ]). The complexes have been completely characterized in solution and the crystal structures of [Pt-BFZ] and [Pt-CTZ] have been resolved. Complexes [Pt-MeIm] and [Pt-BFZ] present higher cytotoxicity than cisplatin in SW480 (colon adenocarcinoma), A549 (lung adenocarcinoma) and A2780 (ovarian cancer) cell lines. [Pt-MeIm] shows the highest accumulation in A549 cells, in agreement with its inability to interact with serum albumin. By contrast, [Pt-CTZ] and [Pt-BFZ] interact with serum proteins, a fact that reduces their bioavailability. The strongest interaction with bovine serum albumin (BSA) is found for [Pt-BFZ], which is the least internalized inside the cells. All the complexes are able to covalently interact with DNA. The most cytotoxic complexes, [Pt-MeIm] and [Pt-BFZ] induce cellular accumulation in G0/G1 and apoptosis by a similar pathway, probably involving a reactive oxygen species (ROS) generation mechanism. [Pt-BFZ] turns out to be the most efficient complex regarding ROS generation and causes mitochondrial membrane depolarization, whereas [Pt-MeIm] induces the opposite effect, hyperpolarization of the mitochondrial membrane. On the contrary, the least cytotoxic complex, [Pt-CTZ] cannot block the cell cycle or generate ROS and the mechanism by which it induces apoptosis could be a different one. La Caixa Foundation (LCF/PR/PR12/11070003), Consejería de Educación-Junta de Castilla y León-FEDER (BU042U16-BU305P18), Ministerio de Ciencia, Innovación y Universidades (RTI2018-102040-B-100). M.V. is grateful for the financial support received from the Consejería de Educación-Junta de Castilla y León-FEDER (BU042U16-BU305P18). 2021-12-02T09:29:29Z 2021-12-02T09:29:29Z 2022-01 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 0162-0134 http://hdl.handle.net/10259/6253 10.1016/j.jinorgbio.2021.111663 eng Journal of Inorganic Biochemistry. 2022, V. 226, 111663 https://doi.org/10.1016/j.jinorgbio.2021.111663 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-102040-B-I00/ES/PROPIEDADES ANTIMICROBIANAS DE NUEVOS COMPLEJOS ORGANOMETALICOS info:eu-repo/grantAgreement/Junta de Castilla y León//BU042U16 info:eu-repo/grantAgreement/Junta de Castilla y León//BU305P18 info:eu-repo/grantAgreement/Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona//LCF%2FPR%2FPR12%2F11070003 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Elsevier